1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one Derivatives Useful As Factor XIa Inhibitors

ABSTRACT

The present invention is directed to 1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one derivatives, stereoisomers, isotopologues, and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing said compounds and the use of said compounds in the treatment and/or prophylaxis of thromboembolic disorders, inflammatory disorders and diseases or conditions in which plasma kallikrein activity is implicated.

FIELD OF THE INVENTION

The present invention is directed1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one derivatives,stereoisomers, isotopologues, and pharmaceutically acceptable saltsthereof, pharmaceutical compositions containing said compounds, and theuse of said compounds in the treatment and/or prophylaxis ofthromboembolic disorders, inflammatory disorders and diseases orconditions in which plasma kallikrein activity is implicated.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), andsynthetic penta-saccharides and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®). The oral anticoagulant warfarin inhibits thepost-translational maturation of coagulation factors VII, IX, X andprothrombin, and has proven effective in both venous and arterialthrombosis. However, its usage is limited due to its narrow therapeuticindex with respect to bleeding safety, slow onset of therapeutic effect,numerous dietary and drug-drug interactions, and a need for monitoringand dose adjustment. Novel oral anticoagulants directly targeting eitherthrombin or factor Xa, e.g., dabigatran, apixaban, betrixaban, edoxaban,rivaroxaban, have been approved for both venous and arterialindications. However, the risk of bleeding is not completely eliminated,and can be as high as 2-3% per year in patients with atrial fibrillation(Quan et al., J. Med. Chem. 2018, pp 7425-7447, Vol. 61). Thus,discovering and developing safe and efficacious oral anticoagulants withminimal impacts on hemostasis for the prevention and treatment of a widerange of thromboembolic disorders has become increasingly important.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein

R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl,fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, cyano, nitro,—NR^(A)R^(B), —C(O)—C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl and 5 to 6membered heterocyclyl;

wherein the C₃₋₆cycloalkyl, phenyl or 5 to 6 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of halogen, hydroxy, cyano,C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy,—C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B), —(C₁₋₄alkylene)-NR^(A)R^(B),C₃₋₇cycloalkyl and 5 to 6 membered heterocyclyl;

and wherein R^(A) and R^(B) are each independently selected from thegroup consisting of hydrogen and C₁₋₄alkyl;

a is an integer from 0 to 3;

each R² is independently selected from the group consisting of chloro,fluoro, methyl and methoxy;

Q is selected from the group consisting of

wherein R⁴ is selected from the group consisting of hydrogen, andhalogen;

wherein R⁵ is selected from the group consisting of phenyl and 5 to 6membered heteroaryl;

wherein the phenyl or 5 to 6 membered heteroaryl is optionallysubstituted with one to two substituents independently selected from thegroup consisting of halogen, C₁₋₄alkyl, fluorinated C₁₋₂alkyl, hydroxysubstituted C₁₋₂alkyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(C)R^(D),—C(O)—NR^(C)R^(D) and —NR^(C)—C(O)—(C₁₋₂alkyl); and wherein R^(C) andR^(D) are each independently selected from the group consisting ofhydrogen, C₁₋₂alkyl and hydroxy substituted C₁₋₄alkyl;

and

wherein R⁶ is selected from the group consisting of phenyl and 9 to 10membered heteroaryl;

wherein the phenyl or 9 to 10 membered heteroaryl is optionallysubstituted with one to two substituents independently selected from thegroup consisting of halogen, C₁₋₄alkyl, fluorinated C₁₋₂alkyl, hydroxysubstituted C₁₋₂alkyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(C)R^(D),—C(O)—NR^(E)R^(F), and —NR^(C)—C(O)—(C₁₋₂alkyl); wherein R^(E) and R^(F)are each independently selected from the group consisting of hydrogenand C₁₋₄alkyl;

and stereoisomers, isotopologues, and pharmaceutically acceptable saltsthereof.

The present invention is further directed to processes for thepreparation of the compounds of formula (I). The present invention isfurther directed to a compound of formula (I) prepared according to anyof the process(es) described herein.

Illustrative of the invention are pharmaceutical compositions comprisinga pharmaceutically acceptable carrier and a compound of formula (I) asdescribed herein. An illustration of the invention is a pharmaceuticalcomposition made by mixing a compound of formula (I) as described hereinand a pharmaceutically acceptable carrier. Illustrating the invention isa process for making a pharmaceutical composition comprising mixing acompound of formula (I) as described herein and a pharmaceuticallyacceptable carrier.

Exemplifying the invention are methods for the treatment and/orprophylaxis of thromboembolic disorders, inflammatory disorders ordiseases or conditions in which plasma kallikrein activity isimplicated, as described herein, comprising administering to a subjectin need thereof a therapeutically effective amount of any of thecompounds or pharmaceutical compositions described above.

Exemplifying the invention are methods or the treatment and/orprophylaxis of thromboembolic disorders, such as arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, arterial cerebrovascular thromboembolic disorders, and venouscerebrovascular thromboembolic disorders, comprising administering to asubject in need thereof a therapeutically effective amount of any of thecompounds or pharmaceutical compositions described above. Examples ofthromboembolic disorders include, but are not limited to, unstableangina, an acute coronary syndrome, atrial fibrillation, firstmyocardial infarction, recurrent myocardial infarction, ischemic suddendeath, transient ischemic attack, stroke, atherosclerosis, peripheralocclusive arterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis.

In an embodiment, the present invention is directed to a compound offormula (I) for use as a medicament. In another embodiment, the presentinvention is directed to a compound of formula (I) for use in thetreatment and/or prophylaxis of thromboembolic disorders, inflammatorydisorders or diseases or conditions in which plasma kallikrein activityis implicated.

In another embodiment, the present invention is directed to a compoundof formula (I) for use in the treatment and/or prophylaxis of athromboembolic disorder, such as arterial cardiovascular thromboembolicdisorders, venous cardiovascular thromboembolic disorders, arterialcerebrovascular thromboembolic disorders, and venous cerebrovascularthromboembolic disorders. In another embodiment, the present inventionis directed to a compound of formula (I) for use in the treatment and/orprophylaxis of a thromboembolic disorder selected from the groupconsisting of unstable angina, an acute coronary syndrome, atrialfibrillation, first myocardial infarction, recurrent myocardialinfarction, ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention is directed to a compound of formula(I) for use in the treatment and/or prophylaxis of a thromboembolicdisorder selected from the group consisting of hereditary angioedema(HAE) and diabetic macular edema (DME).

In another embodiment, the present invention is directed to acomposition comprising a compound of formula (I) for use in thetreatment and/or prophylaxis of a disorder, disease or condition asdescribed herein. In another embodiment, the present invention isdirected to a composition comprising a compound of formula (I) for usein the treatment and/or prophylaxis of a thromboembolic disorder, andinflammatory disorder or a disease or condition in which plasmakallikrein activity is implicated.

In another embodiment, the present invention is directed to acomposition comprising a compound of formula (I) for use in thetreatment and/or prophylaxis of a thromboembolic disorder, such asarterial cardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, arterial cerebrovascular thromboembolicdisorders, and venous cerebrovascular thromboembolic disorders. Inanother embodiment, the present invention is directed to a compositioncomprising a compound of formula (I) for use in the treatment and/orprophylaxis of a thromboembolic disorder selected from the groupconsisting of unstable angina, an acute coronary syndrome, atrialfibrillation, first myocardial infarction, recurrent myocardialinfarction, ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention is directed to a compositioncomprising a compound of formula (I) for use in the treatment and/orprophylaxis of a thromboembolic disorder such as hereditary angioedema(HAE) or diabetic macular edema (DME).

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for the treatmentand/or prophylaxis of a disorder, disease or condition as describedherein. Another example of the invention is the use of any of thecompounds described herein in the preparation of a medicament for thetreatment and/or prophylaxis of a thromboembolic disorder, aninflammatory disorder or a disease or condition in which plasmakallikrein activity is implicated.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for the treatmentand/or prophylaxis of a thromboembolic disorder selected from the groupconsisting of (a) arterial cardiovascular thromboembolic disorders, (b)venous cardiovascular thromboembolic disorders, (c) arterialcerebrovascular thromboembolic disorders, and (d) venous cerebrovascularthromboembolic disorders. Another example of the invention is the use ofany of the compounds described herein in the preparation of a medicamentfor the treatment and/or prophylaxis of (a) unstable angina, (b) anacute coronary syndrome, (c) atrial fibrillation, (d) first myocardialinfarction, (e) recurrent myocardial infarction, (f) ischemic suddendeath, (g) transient ischemic attack, (h) stroke, (i) atherosclerosis,(j) peripheral occlusive arterial disease, (k) venous thrombosis, (l)deep vein thrombosis, (m) thrombophlebitis, (n) arterial embolism, (o)coronary arterial thrombosis, (p) cerebral arterial thrombosis, (q)cerebral embolism, (r) kidney embolism, (s) pulmonary embolism, or (t)thrombosis resulting from medical implants, devices, or procedures inwhich blood is exposed to an artificial surface that promotesthrombosis. Another example of the invention is the use of any of thecompounds described herein in the preparation of a medicament for thetreatment and/or prophylaxis of: (a) hereditary angioedema (HAE) or (b)diabetic macular edema (DME).

Another example of the invention is the use of any of the compoundsdescribed herein for use in a method for treating a thromboembolic,inflammatory or a disease or condition in which plasma kallikreinactivity is implicated as described herein, in a subject in needthereof.

Another example of the invention is the use of any of the compoundsdescribed herein for use in a method for the treatment and/orprophylaxis of (a) arterial cardiovascular thromboembolic disorders, (b)venous cardiovascular thromboembolic disorders, (c) arterialcerebrovascular thromboembolic disorders, or (d) venous cerebrovascularthromboembolic disorders, in a subject in need thereof. Another exampleof the invention is the use of any of the compounds described herein foruse in a method for the treatment and/or prophylaxis of (a) unstableangina, (b) an acute coronary syndrome, (c) atrial fibrillation, (d)first myocardial infarction, (e) recurrent myocardial infarction, (f)ischemic sudden death, (g) transient ischemic attack, (h) stroke, (i)atherosclerosis, (j) peripheral occlusive arterial disease, (k) venousthrombosis, (1) deep vein thrombosis, (m) thrombophlebitis, (n) arterialembolism, (o) coronary arterial thrombosis, (p) cerebral arterialthrombosis, (q) cerebral embolism, (r) kidney embolism, (s) pulmonaryembolism, or (t) thrombosis resulting from medical implants, devices, orprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis, in a subject in need thereof. Another example ofthe invention is the use of any of the compounds described herein foruse in a method for the treatment and/or prophylaxis of (a) hereditaryangioedema (HAE) or (b) diabetic macular edema (DME), in a subject inneed thereof.

In another example, the present invention is directed to a compound asdescribed herein, for use in a method for the treatment and/orprophylaxis of disorders, diseases or conditions as described herein, ina subject in need thereof. In another example, the present invention isdirected to a compound as described herein, for use in a method for thetreatment and/or prophylaxis of a thromboembolic, inflammatory disorder,or a disease or condition in which plasma kallikrein activity isimplicated, as described herein, in a subject in need thereof.

In another example, the present invention is directed to a compound asdescribed herein, for use in methods for the treatment and/orprophylaxis of thromboembolic disorder, such as arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, arterial cerebrovascular thromboembolic disorders, and venouscerebrovascular thromboembolic disorders, in a subject in need thereof.In another example, the present invention is directed to a compound asdescribed herein, for use in methods for the treatment and/orprophylaxis of unstable angina, an acute coronary syndrome, atrialfibrillation, first myocardial infarction, recurrent myocardialinfarction, ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis, in a subject in needthereof. In another example, the present invention is directed to acompound as described herein, for use in a method for the treatmentand/or prophylaxis of hereditary angioedema (HAE) or diabetic macularedema (DME), in a subject in need thereof.

The present invention is further directed to a compound, composition(e.g. pharmaceutical composition), method of treatment, method ofpreparation or use, as herein described.

DETAILED DESCRIPTION OF THE INVENTION 1.1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one Derivatives

Factor XIa is a plasma serine protease involved in the regulation ofblood coagulation. While blood coagulation is a necessary and importantpart of the regulation of an organism's homeostasis, abnormal bloodcoagulation can also have deleterious effects. For instance, thrombosisis the formation or presence of a blood clot inside a blood vessel orcavity of the heart. Such a blood clot can lodge in a blood vesselblocking circulation and causing a heart attack or stroke.Thromboembolic disorders are the leading cause of mortality anddisability in the industrialized world.

Blood clotting is a process of control of the bloodstream essential forthe survival of mammals. The process of clotting, and the subsequentdissolution of the clot after wound healing has taken place, commencesafter vascular injury, and can be divided into four phases. The firstphase, vasoconstriction or vasocontraction, can cause a decrease inblood loss in the injured area. In the next phase, platelet activationby thrombin, platelets attach to the site of the vessel wall damage andform a platelet aggregate. In the third phase, formation of clottingcomplexes leads to massive formation of thrombin, which converts solublefibrinogen to fibrin by cleavage of two small peptides. In the fourthphase, after wound healing, the thrombus is dissolved by the action ofthe key enzyme of the endogenous fibrinolysis system, plasmin.

Two alternative pathways can lead to the formation of a fibrin clot, theintrinsic and the extrinsic pathway. These pathways are initiated bydifferent mechanisms, but in the later phase they converge to give acommon final path of the clotting cascade. In this final path ofclotting, clotting Factor X is activated. The activated Factor X isresponsible for the formation of thrombin from the inactive precursorprothrombin circulating in the blood. The formation of a thrombus on thebottom of a vessel wall abnormality without a wound is the result of theintrinsic pathway. Fibrin clot formation as a response to tissue injuryor an injury is the result of the extrinsic pathway. Both pathwayscomprise a relatively large number of proteins, which are known asclotting factors. The intrinsic pathway requires the clotting Factors V,VIII, IX, X, XI and XII and also prekallikrein, high molecular weightkininogen, calcium ions and phospholipids from platelets.

Factor XIa, a plasma serine protease involved in the regulation of bloodcoagulation, is initiated in vivo by the binding of tissue Factor (TF)to factor VII (FVII) to generate Factor VIIa (FVIIa). The resultingTF:FVIIa complex activates Factor IX (FIX) and Factor X (FX) that leadsto the production of Factor Xa (FXa). The generated FXa catalyzes thetransformation of prothrombin into small amounts of thrombin before thispathway is shut down by tissue factor pathway inhibitor (TFPI). Theprocess of coagulation is then further propagated via the feedbackactivation of Factors V, VIII and XI by catalytic amounts of thrombin.(Gailani, D. et al., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513(2007)). The resulting burst of thrombin converts fibrinogen to fibrinthat polymerizes to form the structural framework of a blood clot, andactivates platelets, which are a key cellular component of coagulation(Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). FactorXIa plays a keyrole in propagating this amplification loop. Epidemiological studiesshowed that increased circulating FXI levels in humans have beenassociated with increased risk for venous and arterial thrombosis,including stroke (se Quan et al. supra). In contrast, patients withcongenital FXI deficiency (hemophilia C) are protected from ischemicstroke and venous thromboembolism. Therefore, Factor XIa is anattractive target for antithrombotic therapy.

In addition to stimulation via tissue factor, the coagulation system canbe activated particularly on negatively charged surfaces, which includenot only surface structures of foreign cells (e.g. bacteria) but alsoartificial surfaces such as vascular prostheses, stents andextracorporeal circulation. On the surface, initially Factor XII (FXII)is activated to Factor XIIa which subsequently activates Factor XI,attached to cell surfaces, to Factor XIa. This leads to furtheractivation of the coagulation cascade as described above. In addition,Factor XIIa also activates bound plasma prokallikrein to plasmakallikrein (PK) which, in a potentiation loop, leads to further FactorXII activation, overall resulting in amplification of the initiation ofthe coagulation cascade. In addition, PK is an importantbradykinin-releasing protease which leads to increased endothelialpermeability. Further substrates that have been described are proreninand prourokinase, whose activation may influence the regulatoryprocesses of the renin-angiotensin system and fibrinolysis. Theactivation of PK is therefore an important link between coagulative andinflammatory processes.

Embodiments

The present invention is directed to compounds of formula (I)

wherein a, R¹, R², Q, etc. are as described herein; and stereoisomers,isotopologues, and pharmaceutically acceptable salts thereof. Thecompounds of the present invention are useful for the treatment and/orprophylaxis of thromboembolic disorders, inflammatory disorders anddiseases or conditions in which plasma kallikrein activity isimplicated.

In some embodiments, the present invention is directed to compounds offormula (I) of the structure (I-A)

wherein

R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl,fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, cyano, nitro,—NR^(A)R^(B), —C(O)—C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl and 5 to 6membered heterocyclyl; wherein the C₃₋₆cycloalkyl, phenyl or 5 to 6membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, cyano, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy,fluorinated C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B),—(C₁₋₄alkylene)-NR^(A)R^(B), C₃₋₇cycloalkyl and 5 to 6 memberedheterocyclyl; and wherein R^(A) and R^(B) are each independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl;

a is an integer from 0 to 3;

each R² is independently selected from the group consisting of chloro,fluoro, methyl and methoxy;

R⁴ is selected from the group consisting of hydrogen, and halogen;

R⁵ is selected from the group consisting of phenyl and 5 to 6 memberedheteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, C₁₋₄alkyl, fluorinatedC₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl),—NR^(C)R^(D), —C(O)—NR^(C)R^(D) and —NR^(C)—C(O)—(C₁₋₂alkyl); andwherein R^(C) and R^(D) are each independently selected from the groupconsisting of hydrogen, C₁₋₂alkyl and hydroxy substituted C₁₋₄alkyl; andstereoisomers, isotopologues, and pharmaceutically acceptable saltsthereof. In some embodiments, the present invention is directed tocompounds of formula (I) of the structure (I-B)

wherein

R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl,fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy, cyano, nitro,—NR^(A)R^(B), —C(O)—C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl and 5 to 6membered heterocyclyl; wherein the C₃₋₆cycloalkyl, phenyl or 5 to 6membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, cyano, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy,fluorinated C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B),—(C₁₋₄alkylene)-NR^(A)R^(B), C₃₋₇cycloalkyl and 5 to 6 memberedheterocyclyl; and wherein R^(A) and R^(B) are each independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl;

a is an integer from 0 to 3;

each R² is independently selected from the group consisting of chloro,fluoro, methyl and methoxy;

R⁶ is selected from the group consisting of phenyl and 9 to 10 memberedheteroaryl; wherein the phenyl or 9 to 10 membered heteroaryl isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, C₁₋₄alkyl, fluorinatedC₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl),—NR^(C)R^(D), —C(O)—NR^(E)R^(F), and —NR^(C)—C(O)—(C₁₋₂alkyl); whereinR^(E) and R^(F) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl;

and stereoisomers, isotopologues, and pharmaceutically acceptable saltsthereof.

In some embodiments, the present invention is directed to compounds offormula (I) wherein

R¹ is selected from the group consisting of halogen, hydroxy, C₁₋₄alkyl,fluorinated C₁₋₂alkyl, C₁₋₄alkoxy, fluorinated C₁₋₂alkoxy,C₃₋₆cycloalkyl, phenyl and 5 to 6 membered heterocyclyl; wherein theC₃₋₆cycloalkyl, phenyl or 5 to 6 membered heterocyclyl is optionallysubstituted with one to two substituents independently selected from thegroup consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₂alkyl,C₁₋₄alkoxy, fluorinated C₁₋₂alkoxy, —C(O)OH, and —C(O)O—(C₁₋₄alkyl);

a is an integer from 0 to 2;

each R² is independently selected from the group consisting of chloro,fluoro, methyl and methoxy;

Q is selected from the group consisting of

wherein R⁴ is selected from the group consisting of hydrogen, andhalogen;

wherein R⁵ is selected from the group consisting of phenyl and 5 to 6membered heteroaryl; wherein the phenyl or 5 to 6 membered heteroaryl isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, C₁₋₄alkyl, fluorinatedC₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl),—NR^(C)R^(D), —C(O)—NR^(C)R^(D) and —NR^(C)—C(O)—(C₁₋₂alkyl); andwherein R^(C) and R^(D) are each independently selected from the groupconsisting of hydrogen, C₁₋₂alkyl and hydroxy substituted C₁₋₄alkyl;

and

wherein R⁶ is selected from the group consisting of phenyl and 9 to 10membered heteroaryl; wherein the phenyl or 9 to 10 membered heteroarylis optionally substituted with one to two substituents independentlyselected from the group consisting of halogen, C₁₋₄alkyl, fluorinatedC₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl),and —C(O)—NR^(E)R^(F); wherein R^(E) and R^(F) are each independentlyselected from the group consisting of hydrogen and C₁₋₂alkyl;

and stereoisomers, isotopologues, and pharmaceutically acceptable saltsthereof.

In some embodiments, the present invention is directed to compounds offormula (I) wherein

R¹ is selected from the group consisting of fluorinated C₁₋₂alkoxy, and5 to 6 membered heterocyclyl; wherein the 5 to 6 membered heterocyclylis optionally substituted with fluorinated C₁₋₂alkyl;

a is an integer from 1 to 2;

each R² is independently selected from the group consisting of chloro,and fluoro;

Q is selected from the group consisting of

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;

wherein R⁵ is selected from the group consisting of phenyl and 6membered heteroaryl; wherein the phenyl or 6 membered heteroaryl isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, hydroxy substitutedC₁₋₂alkyl, —C(O)OH, —NR^(C)R^(D), —C(O)—NR^(C)R^(D) and—NR^(C)—C(O)—(C₁₋₂alkyl); wherein R^(C) and R^(D) are each independentlyselected from the group consisting of hydrogen, C₁₋₂alkyl and hydroxysubstituted C₁₋₄alkyl;

and

wherein R⁶ is selected from the group consisting of phenyl and 9 to 10membered heteroaryl; wherein the phenyl or 9 to 10 membered heteroarylis optionally substituted with one to two substituents independentlyselected from the group consisting of halogen, fluorinated C₁₋₂alkyl,—C(O)OH) and —C(O)—NR^(E)R^(F); wherein R^(E) and R^(F) are eachindependently selected from the group consisting of hydrogen andC₁₋₂alkyl;

and stereoisomers, isotopologues, and pharmaceutically acceptable saltsthereof.

In some embodiments, the present invention is directed to compounds offormula (I) wherein

R¹ is selected from the group consisting of difluoro-methoxy,4-(trifluoromethyl)-1,2,3-triazol-1-yl, and 1,2,3,4-tetrazol-1-yl;

a is an integer from 1 to 2;

each R² is independently selected from the group consisting of 2-fluoroand 3-chloro;

Q is selected from the group consisting of

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;

wherein R⁵ is selected from the group consisting of2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-6-amino-pyridin-3-yl,2-((2-hydroxy,2-methyl-n-propyl)-amino)-3-fluoro-pyridin-3-yl,2-carboxy-3-fluoro-pyridin-4-yl,2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-amino-3-fluoro-pyridin-4-yl,2-(ethyl-amino)-3-fluoro-pyridin-4-yl, and2-(methyl-carbonyl-amino)-3-fluoro-pyridin-4-yl;

and

wherein R⁶ is selected from the group consisting of 4-carboxy-phenyl,3-fluoro-4-(amino-carbonyl)-phenyl, 2-(difluoro-methyl)-indazol-5-yl,and quinoxalin-6-yl;

and stereoisomers, isotopologues, and pharmaceutically acceptable saltsthereof.

In some embodiments, the present invention is directed to compounds offormula (I) wherein

R¹ is selected from the group consisting of4-(trifluoromethyl)-1,2,3-triazol-1-yl, and 1,2,3,4-tetrazol-1-yl;

a is an integer from 1 to 2;

each R² is independently selected from the group consisting of 2-fluoroand 3-chloro;

Q is

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;

wherein R⁵ is selected from the group consisting of2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-6-amino-pyridin-3-yl,2-((2-hydroxy,2-methyl-n-propyl)-amino)-3-fluoro-pyridin-3-yl,2-carboxy-3-fluoro-pyridin-4-yl,2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-amino-3-fluoro-pyridin-4-yl,2-(ethyl-amino)-3-fluoro-pyridin-4-yl, and2-(methyl-carbonyl-amino)-3-fluoro-pyridin-4-yl; and stereoisomers,isotopologues, and pharmaceutically acceptable salts thereof.

In some embodiments, the present invention is directed to compounds offormula (I) wherein

R¹ is selected from the group consisting of difluoro-methoxy, and1,2,3,4-tetrazol-1-yl;

a is 2; the two R² are 2-fluoro and 3-chloro;

Q is

wherein R⁶ is selected from the group consisting of 4-carboxy-phenyl,3-fluoro-4-(amino-carbonyl)-phenyl, 2-(difluoro-methyl)-indazol-5-yl,and quinoxalin-6-yl;

and stereoisomers, isotopologues, and pharmaceutically acceptable saltsthereof.

In some embodiments, the present invention is directed to compounds offormula (I) wherein

R¹ is selected from the group consisting of difluoro-methoxy,4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl;

a is an integer from 1 to 2;

each R² is independently selected from the group consisting of 2-fluoroand 3-chloro;

Q is selected from the group consisting of

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;

wherein R⁵ is selected from the group consisting of2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-6-amino-pyridin-3-yl,2-((2-hydroxy,2-methyl-n-propyl)-amino)-3-fluoro-pyridin-3-yl,2-carboxy-3-fluoro-pyridin-4-yl, 2-amino-3-fluoro-pyridin-4-yl, and2-(ethyl-amino)-3-fluoro-pyridin-4-yl;

and

wherein R⁶ is selected from the group consisting of3-fluoro-4-(amino-carbonyl)-phenyl, 2-(difluoro-methyl)-indazol-5-yl,and quinoxalin-6-yl;

and stereoisomers, isotopologues, and pharmaceutically acceptable saltsthereof.

In some embodiments, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting of halogen,hydroxy, C₁₋₄alkyl, fluorinated C₁₋₂alkyl, C₁₋₄alkoxy, fluorinatedC₁₋₂alkoxy, C₃₋₆cycloalkyl, phenyl and 5 to 6 membered heterocyclyl;wherein the C₃₋₆cycloalkyl, phenyl or 5 to 6 membered heterocyclyl isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, hydroxy, C₁₋₄alkyl,fluorinated C₁₋₂alkyl, C₁₋₄alkoxy, fluorinated C₁₋₂alkoxy, —C(O)OH, and—C(O)O—(C₁₋₄alkyl). In some embodiments, the present invention isdirected to compounds of formula (I) wherein R¹ is selected from thegroup consisting of fluorinated C₁₋₂alkoxy, and 5 to 6 memberedheterocyclyl; wherein the 5 to 6 membered heterocyclyl is optionallysubstituted with fluorinated C₁₋₂alkyl.

In some embodiments, the present invention is directed to compounds offormula (I) wherein R¹ is selected from the group consisting ofdifluoromethoxy, 4-(trifluoromethyl)-1,2,3-triazol-1-yl, and1,2,3,4-tetrazol-1-yl. In some embodiments, the present invention isdirected to compounds of formula (I) wherein R¹ is selected from thegroup consisting of difluoromethoxy, and 1,2,3,4-tetrazol-1-yl. In someembodiments, the present invention is directed to compounds of formula(I) wherein R¹ is selected from the group consisting of4-(trifluoromethyl)-1,2,3-triazol-1-yl, and 1,2,3,4-tetrazol-1-yl.

In some embodiments, the present invention is directed to compounds offormula (I) wherein a is an integer from 0 to 2. In some embodiments,the present invention is directed to compounds of formula (I) wherein ais an integer from 1 to 3. In some embodiments, the present invention isdirected to compounds of formula (I) wherein a is an integer from 1 to2. In some embodiments, the present invention is directed to compoundsof formula (I) wherein a is 0. In some embodiments, the presentinvention is directed to compounds of formula (I) wherein a is 1. Insome embodiments, the present invention is directed to compounds offormula (I) wherein a is 2. In some embodiments, the present inventionis directed to compounds of formula (I) wherein a is 3.

In some embodiments, the present invention is directed to compounds offormula (I) wherein each R² is independently selected from the groupconsisting of chloro, fluoro, methyl and methoxy. In some embodiments,the present invention is directed to compounds of formula (I) whereineach R² is independently selected from the group consisting of chloro,and fluoro. In some embodiments, the present invention is directed tocompounds of formula (I) wherein each R² is independently selected fromthe group consisting of 2-fluoro and 3-chloro. In some embodiments, thepresent invention is directed to compounds of formula (I) wherein two R²groups are present and are 2-fluoro and 3-chloro.

In some embodiments, the present invention is directed to compounds offormula (I) wherein Q is selected from the group consisting of

wherein R⁴ is selected from the group consisting of hydrogen, andhalogen; wherein R⁵ is selected from the group consisting of phenyl and5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 memberedheteroaryl is optionally substituted with one to two substituentsindependently selected from the group consisting of halogen, C₁₋₄alkyl,fluorinated C₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH,—C(O)O—(C₁₋₄alkyl), —NR^(C)R^(D), —C(O)—NR^(C)R^(D) and—NR^(C)—C(O)—(C₁₋₂alkyl); and wherein R^(C) and R^(D) are eachindependently selected from the group consisting of hydrogen, C₁₋₂alkyland hydroxy substituted C₁₋₄alkyl; and

wherein R⁶ is selected from the group consisting of phenyl and 9 to 10membered heteroaryl; wherein the phenyl or 9 to 10 membered heteroarylis optionally substituted with one to two substituents independentlyselected from the group consisting of halogen, C₁₋₄alkyl, fluorinatedC₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl),and —C(O)—NR^(E)R^(F); wherein R^(E) and R^(F) are each independentlyselected from the group consisting of hydrogen and C₁₋₂alkyl.

In some embodiments, the present invention is directed to compounds offormula (I) wherein Q is selected from the group consisting of

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;wherein R⁵ is selected from the group consisting of phenyl and 6membered heteroaryl; wherein the phenyl or 6 membered heteroaryl isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, hydroxy substitutedC₁₋₂alkyl, —C(O)OH, —NR^(C)R^(D), —C(O)—NR^(C)R^(D) and—NR^(C)—C(O)—(C₁₋₂alkyl); wherein R^(C) and R^(D) are each independentlyselected from the group consisting of hydrogen, C₁₋₂alkyl and hydroxysubstituted C₁₋₄alkyl; and

wherein R⁶ is selected from the group consisting of phenyl and 9 to 10membered heteroaryl; wherein the phenyl or 9 to 10 membered heteroarylis optionally substituted with one to two substituents independentlyselected from the group consisting of halogen, fluorinated C₁₋₂alkyl,—C(O)OH) and —C(O)—NR^(E)R^(F); wherein R^(E) and R^(F) are eachindependently selected from the group consisting of hydrogen andC₁₋₂alkyl.

In some embodiments, the present invention is directed to compounds offormula (I) wherein Q is selected from the group consisting of (a)

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;wherein R⁵ is selected from the group consisting of2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-6-amino-pyridin-3-yl,2-((2-hydroxy,2-methyl-n-propyl)-amino)-3-fluoro-pyridin-3-yl,2-carboxy-3-fluoro-pyridin-4-yl,2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-amino-3-fluoro-pyridin-4-yl,2-(ethyl-amino)-3-fluoro-pyridin-4-yl, and2-(methyl-carbonyl-amino)-3-fluoro-pyridin-4-yl; and

wherein R⁶ is selected from the group consisting of 4-carboxy-phenyl,3-fluoro-4-(amino-carbonyl)-phenyl, 2-(difluoro-methyl)-indazol-5-yl,and quinoxalin-6-yl.

In some embodiments, the present invention is directed to compounds offormula (I) wherein Q is selected from the group consisting of

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;wherein R⁵ is selected from the group consisting of2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-6-amino-pyridin-3-yl,2-((2-hydroxy,2-methyl-n-propyl)-amino)-3-fluoro-pyridin-3-yl,2-carboxy-3-fluoro-pyridin-4-yl, 2-amino-3-fluoro-pyridin-4-yl, and2-(ethyl-amino)-3-fluoro-pyridin-4-yl; and

wherein R⁶ is selected from the group consisting of3-fluoro-4-(amino-carbonyl)-phenyl, 2-(difluoro-methyl)-indazol-5-yl,and quinoxalin-6-yl.

In some embodiments, the present invention is directed to compounds offormula (I) wherein Q is

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;wherein R⁵ is selected from the group consisting of2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-6-amino-pyridin-3-yl,2-((2-hydroxy,2-methyl-n-propyl)-amino)-3-fluoro-pyridin-3-yl,2-carboxy-3-fluoro-pyridin-4-yl,2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-amino-3-fluoro-pyridin-4-yl,2-(ethyl-amino)-3-fluoro-pyridin-4-yl, and2-(methyl-carbonyl-amino)-3-fluoro-pyridin-4-yl.

In some embodiments, the present invention is directed to compounds offormula (I) wherein Q is

wherein R⁶ is selected from the group consisting of 4-carboxy-phenyl,3-fluoro-4-(amino-carbonyl)-phenyl, 2-(difluoro-methyl)-indazol-5-yl,and quinoxalin-6-yl.

In some embodiments, the present invention is directed to compounds offormula (I) wherein R⁴ is selected from the group consisting ofhydrogen, and halogen. In some embodiments, the present invention isdirected to compounds of formula (I) wherein R⁴ is selected from thegroup consisting of hydrogen and fluoro. In some embodiments, thepresent invention is directed to compounds of formula (I) wherein R⁴ ishydrogen. In some embodiments, the present invention is directed tocompounds of formula (I) wherein R⁴ is fluoro.

In some embodiments, the present invention is directed to compounds offormula (I) wherein R⁵ is selected from the group consisting of phenyland 5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 memberedheteroaryl is optionally substituted with one to two substituentsindependently selected from the group consisting of halogen, C₁₋₄alkyl,fluorinated C₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH,—C(O)O—(C₁₋₄alkyl), —NR^(C)R^(D), —C(O)—NR^(C)R^(D) and—NR^(C)—C(O)—(C₁₋₂alkyl); and wherein R^(C) and R^(D) are eachindependently selected from the group consisting of hydrogen, C₁₋₂alkyland hydroxy substituted C₁₋₄alkyl. In some embodiments, the presentinvention is directed to compounds of formula (I) wherein R⁵ is selectedfrom the group consisting of phenyl and 6 membered heteroaryl; whereinthe phenyl or 6 membered heteroaryl is optionally substituted with oneto two substituents independently selected from the group consisting ofhalogen, hydroxy substituted C₁₋₂alkyl, —C(O)OH, —NR^(C)R^(D),—C(O)—NR^(C)R^(D) and —NR^(C)—C(O)—(C₁₋₂alkyl); wherein R^(C) and R^(D)are each independently selected from the group consisting of hydrogen,C₁₋₂alkyl and hydroxy substituted C₁₋₄alkyl.

In some embodiments, the present invention is directed to compounds offormula (I) wherein R⁵ is selected from the group consisting of2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-6-amino-pyridin-3-yl,2-((2-hydroxy,2-methyl-n-propyl)-amino)-3-fluoro-pyridin-3-yl,2-carboxy-3-fluoro-pyridin-4-yl,2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-amino-3-fluoro-pyridin-4-yl,2-(ethyl-amino)-3-fluoro-pyridin-4-yl, and2-(methyl-carbonyl-amino)-3-fluoro-pyridin-4-yl. In some embodiments,the present invention is directed to compounds of formula (I) wherein R⁵is selected from the group consisting of2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-6-amino-pyridin-3-yl,2-((2-hydroxy,2-methyl-n-propyl)-amino)-3-fluoro-pyridin-3-yl,2-carboxy-3-fluoro-pyridin-4-yl, 2-amino-3-fluoro-pyridin-4-yl, and2-(ethyl-amino)-3-fluoro-pyridin-4-yl.

In some embodiments, the present invention is directed to compounds offormula (I) wherein R⁶ is selected from the group consisting of phenyland 9 to 10 membered heteroaryl; wherein the phenyl or 9 to 10 memberedheteroaryl is optionally substituted with one to two substituentsindependently selected from the group consisting of halogen, C₁₋₄alkyl,fluorinated C₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH,—C(O)O—(C₁₋₄alkyl), and —C(O)—NR^(E)R^(F); wherein R^(E) and R^(F) areeach independently selected from the group consisting of hydrogen andC₁₋₂alkyl. In some embodiments, the present invention is directed tocompounds of formula (I) wherein R⁶ is selected from the groupconsisting of phenyl and 9 to 10 membered heteroaryl; wherein the phenylor 9 to 10 membered heteroaryl is optionally substituted with one to twosubstituents independently selected from the group consisting ofhalogen, fluorinated C₁₋₂alkyl, —C(O)OH) and —C(O)—NR^(E)R^(F); whereinR^(E) and R^(F) are each independently selected from the groupconsisting of hydrogen and C₁₋₂alkyl.

In some embodiments, the present invention is directed to compounds offormula (I) wherein R⁶ is selected from the group consisting of4-carboxy-phenyl, 3-fluoro-4-(amino-carbonyl)-phenyl,2-(difluoro-methyl)-indazol-5-yl, and quinoxalin-6-yl. In someembodiments, the present invention is directed to compounds of formula(I) wherein R⁶ is selected from the group consisting of3-fluoro-4-(amino-carbonyl)-phenyl, 2-(difluoro-methyl)-indazol-5-yl,and quinoxalin-6-yl.

In some embodiments, the present invention is directed to one or morecompounds of formula (I) independently selected from the groupconsisting of

-   4-(2-((3S,9aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-3-fluorobenzamide;-   (3S,9aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamide;-   3S,9aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(quinoxalin-6-yl)-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamide;

and isotopologues and pharmaceutically acceptable salts thereof.

One skilled in the art will recognize that, depending on substituentgroups, the compounds of the present invention may contain one or morestereo-centers, including, for example, the two stereo-centers denotedby the star (“*”) symbols in the structure of the compounds of formula(I) shown below

Unless otherwise noted, the starred (“*”) stereo-center at the bridgecarbon atom of the 1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-onestructure shall be referred to as the “Ring” stereo-center. Similarly,the starred (“*”) stereo-center at the carbon atom of the1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one structure bound tothe Q substituent group shall be referred to as the “Q” stereo-center.

In some embodiments, the present invention is directed to compounds offormula (I) wherein the Ring stereo-center is present as a racemicmixture. In some embodiments, the present invention is directed tocompounds of formula (I) wherein the Ring stereo-center is present in anenantiomeric excess of the corresponding R-enantiomer. In someembodiments, the present invention is directed to compounds of formula(I) wherein the Ring stereocenter is present in an enantiomeric excessof the corresponding S-enantiomer.

In some embodiments, the present invention is directed to compounds offormula (I) wherein the Ring stereo-center is present in anstereo-isomeric excess of either the R- or S-enantiomer of about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%,about 97%, about 98% or about 99%. Preferably, the compound of formula(I) is present in a stereo-isomeric excess at the Ring stereo-center ofgreater than or equal to about 80%, preferably greater than or equal toabout 90%, more preferably greater than or equal to about 93%, morepreferably greater than or equal to about 95%, more preferably greaterthan or equal to about 97%, more preferably greater than or equal toabout 98%, more preferably greater than or equal to about 99%.

In some embodiments, the present invention is directed to compounds offormula (I) wherein the Q stereo-center is present as a racemic mixture.In some embodiments, the present invention is directed to compounds offormula (I) wherein the Q stereo-center is present in an enantiomericexcess of the corresponding R-enantiomer. In some embodiments, thepresent invention is directed to compounds of formula (I) wherein the Qstereocenter is present in an enantiomeric excess of the correspondingS-enantiomer.

In some embodiments, the present invention is directed to compounds offormula (I) wherein the Q stereo-center is present in an stereo-isomericexcess of either the R- or S-enantiomer of about 55%, about 60%, about65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%,about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about98% or about 99%. Preferably, the compound of formula (I) is present ina stereo-isomeric excess at the Ring stereo-center of greater than orequal to about 80%, preferably greater than or equal to about 90%, morepreferably greater than or equal to about 93%, more preferably greaterthan or equal to about 95%, more preferably greater than or equal toabout 97%, more preferably greater than or equal to about 98%, morepreferably greater than or equal to about 99%.

Additional embodiments of the present invention include those whereinthe substituents selected for one or more of the variables definedherein (i.e. a, R¹, R², Q, etc.) are independently selected to be anyindividual substituent or any subset of substituents selected from thecomplete list as defined herein.

Additional embodiments of the present invention include those whereinthe substituents selected for one or more of the variables definedherein (a, R¹, R², Q, etc.) are independently selected to correspond toany of the embodiments as defined herein.

In additional embodiments, the present invention is directed to anysingle compound or subset of compounds independently selected from thelist of representative compounds in Tables 1 and 2, below.

Representative compounds of the present invention are as listed inTables 1 and 2, below. Unless otherwise noted, the position of R²group(s) as listed in the Tables below using the following numberingscheme:

such that the R¹ substituent is bound at the 6-position and the R²substituents are bound at the 2-, 3-, 4- and/or 5-positions of thephenyl group.

In Tables 1 and 2 below, the column headed “Ring Stereo” lists thestereo-orientation at the Ring stereo-center; whereas the column headed“Q Stereo” lists the stereo-orientation at the Q stereo-center.Compounds prepared as racemic mixtures of the designated stereocentersare denoted as “RAC”. The S* and R* designations indicate that althoughthe compound was prepared in an excess of one of the correspondingstereoisomers, the exact stereo-configuration was not determined. The Sand R designations indicate that the compound was prepared in an excessof the corresponding S or R stereoisomer, with the exactstereo-configuration as noted.

TABLE 1 Representative Compounds of Formula (I)

ID Bridge No. R¹ (R²)_(a) Stereo Stereo R⁴ R⁵  1 1,2,3,4- 2-fluoro, R SH 2-fluoro-4-(amino-   tetrazol-1-yl 3-chloro carbonyl)-phenyl  21,2,3,4- 2-fluoro, S S H 2-fluoro-4-(amino-   tetrazol-1-yl 3-chlorocarbonyl)-phenyl  4 1,2,3,4- 3-chloro RAC S fluoro 2-amino-3-fluoro-  tetrazol-1-yl pyridin-4-yl  5 1,2,3,4- 3-chloro RAC S fluoro2-(methyl-carbonyl-   tetrazol-1-yl amino)-3-fluoro-   pyridin-4-yl  64-(trifluoro- 2-fluoro, S S H 2-carboxy-3-fluoro-   methyl)- 3-chloropyridin-4-yl   1,2,3-   triazol-1-yl  7 4-(trifluoro- 3-chloro S S H2-carboxy-3-fluoro-   methyl)- pyridin-4-yl   1,2,3-   triazol-1-yl  81,2,3,4- 3-chloro S S H 2-(ethyl-amino)-3-   tetrazol-1-ylfluoro-pyridin-4-yl  9 1,2,3,4- 3-chloro S S H 2-amino-3-fluoro-tetrazol-1-yl pyridin-4-yl 12 1,2,3,4- 3-chloro S S H 2-((2-hydroxy,2-tetrazol-1-yl methyl-n-propyl)- amino)-3-fluoro- pyridin-3-yl 131,2,3,4- 3-chloro R S H 2-((2-hydroxy,2- tetrazol-1-yl methyl-n-propyl)-amino)-3-fluoro- pyridin-3-yl 14 1,2,3,4- 2-fluoro, R* S H2-fluoro-6-amino- tetrazol-1-yl 3-chloro pyridin-3-yl 15 1,2,3,4-2-fluoro, S* S H 2-fluoro-6-amino- tetrazol-1-yl 3-chloro pyridin-3-yl16 1,2,3,4- 2-fluoro, S S H 2-amino-3-fluoro- tetrazol-1-yl 3-chloropyridin-4-yl 17 1,2,3,4- 2-fluoro, S S H 2-(hydroxy- tetrazol-1-yl3-chloro methyl)-3-fluoro- pyridin-4-yl 22 1,2,3,4- 3-chloro S R* H2-fluoro-6-amino- tetrazol-1-yl pyridin-3-yl 23 1,2,3,4- 3-chloro S S* H2-fluoro-6-amino- tetrazol-1-yl pyridin-3-yl

TABLE 2 Representative Compounds of Formula (I)

Bridge ID No. R¹ (R²)_(a) Stereo Stereo R⁶  3 difluoro- 2-fluoro, S* S*4-carboxy-phenyl methoxy 3-chloro 10 1,2,3,4- 2-fluoro, R S2-(difluoro-methyl)- tetrazol-1-yl 3-chloro indazol-5-yl 11 1,2,3,4-2-fluoro, S S 2-(difluoro-methyl)- tetrazol-1-yl 3-chloro indazol-5-yl18 1,2,3,4- 2-fluoro, R S quinoxalin-6-yl tetrazol-1-yl 3-chloro 191,2,3,4- 2-fluoro, S S quinoxalin-6-yl tetrazol-1-yl 3-chloro 201,2,3,4- 2-fluoro, R S 3-fluoro-4-(amino- tetrazol-1-yl 3-chlorocarbonyl)-phenyl 21 1,2,3,4- 2-fluoro, S S 3-fluoro-4-(amino-tetrazol-1-yl 3-chloro carbonyl)-phenyl

2. General Synthesis Schemes

Compounds of formula (I) of the present invention may be prepared asdescribed in the general synthesis schemes and Examples which followhereinafter, selecting and substituting suitable reagents andconditions, as would be well within the skill of persons versed in theart. Additionally, the preparation of any starting materials used in theschemes and synthesis examples which follow hereinafter is well withinthe skill of persons versed in the art.

Compounds of formula (I) may be prepared from the intermediate compoundof formula (XII)

wherein A¹ is C₁₋₄alkyl, preferably methyl or ethyl; and wherein PG² isa suitably selected oxygen protecting group such as Tf, and the like.Compounds of formula (XII) may be prepared as described in Scheme 1,below.

Accordingly, a suitably substituted compound of formula (V), wherein A¹is a suitably selected C₁₋₄alkyl such as methyl, ethyl, and the like,and wherein PG¹ is a suitably selected nitrogen protecting group such asBoc, and the like, a known compound or compound prepared by knownmethods is reacted with butenyl magnesium bromide, a known compound; ina suitably selected solvent such as THF, 2-Me-THF, and the like; at areduced temperature, such as about −78° C.; to yield the correspondingcompound of formula (VI).

The compound of formula (VI) is reacted with a suitably selectedreducing agent such as a mixture of BF₃.Et₂O and triphenyl silane,triethylsilane, and the like; in a suitably selected solvent such asDCM, chloroform, and the like; at a reduced temperature for example atabout −78° C., with warming to about room temperature; to yield thecorresponding compound of formula (VII).

The compound of formula (VII) is reacted with acryloyl chloride, a knowncompound; in the presence of a suitably selected organic amine base suchas TEA, DIPEA, pyridine, and the like; in a suitably selected solventsuch as THF, DMF, and the like; at a reduced temperature for example atabout −78° C., with warming to about room temperature; to yield thecorresponding compound of formula (VIII).

The compound of formula (VIII) is subjected to ring closure conditions;to yield the corresponding compound of formula (IX). For example, thecompound of formula (VIII) may be reacted with a suitably selectedcatalyst such as Grubbs catalyst, Grubbs 2^(nd) generation catalyst,Hoveyda-Grubbs Catalyst®, and Zhan catalyst, and the like; in a suitablyselected solvent such as DCM, CHCl₃, and the like; at an elevatedtemperature, for example at about 50° C.; to yield the correspondingcompound of formula (IX).

The compound of formula (IX) is reacted with bis(pinacolato)diborane, aknown compound; in the presence of catalyst such as CuCl, Cu₂O, and thelike; in the presence of a suitably selected ligand such as BINAP, andthe like; in the presence of a suitably selected base such as NaOt-Bu,KOt-Bu, and the like; in a suitably selected solvent or mixture ofsolvents, such as a mixture of THF/MeOH, and the like;

and then reacted with peroxide, a known compound; at about roomtemperature; to yield the corresponding compound of formula (X).

The compound of formula (X) is reacted with a suitably selected agentsuch as PCC, MnO₂, Swern oxidation reagents, and the like; in a suitablyselected solvent such as DCM, CHCl₃, and the like; at about roomtemperature; to yield the corresponding compound of formula (XI).

The compound of formula (XI) is reacted to install an oxygen protectinggroup; to yield the corresponding compound of formula (XII). Forexample, the compound of formula (XI) may be reacted withN-phenyl-trifluoromethane sulfonimide, a known compound; in the presenceof a suitably selected organic amine base such as TEA, and the like; ina suitably selected solvent such as DCM, and the like; at about roomtemperature; to yield the corresponding compound of formula (XII)wherein PG² is Tf.

One skilled in the art will recognize that compounds of formula (XII)wherein the ring stereo-center is present in a stereo-isomeric excess ofthe corresponding R- or S-stereo-isomer may be similarly prepared asdescribed in Scheme 1 above.

The resulting stereo-isomerically enriched compound of formula (XII) isthen reacted as described in Schemes 2 below, to yield the correspondingcompound of formula (I) wherein the ring stereo-center is present in astereo-isomeric excess of the corresponding R- or S-stereo-isomer.

Compounds of formula (I-B) may be prepared from the correspondingcompounds of formula (XII) as described in Scheme 2, below.

Accordingly, a suitably substituted compound of formula (XII) is reactedwith a suitably substituted compound of formula (XIII), a known compoundor compound prepared by known methods, in the presence of a suitablyselected catalyst such as Pd(PPh₃)₄, PdCl₂(dppf), Pd₂(dba)₃, and thelike; in the presence of a suitably selected base such as K₂CO₃, Cs₂CO₃,K₃PO₄, and the like; in a suitably selected solvent such as 1,4-dioxane,DMF, toluene, and the like; to yield the corresponding compound offormula (XIV).

The compound of formula (XIV) is reacted with a suitably selected basesuch as LiOH, NaOH, KOH, and the like; in a suitably selected solvent ormixture of solvents such as a mixture of THF/MeOH/H₂O and the like; toyield the corresponding compound of formula (XV).

The compound of formula (XV) is reacted with a suitably substitutedcompound of formula (XVI), a known compound or compound prepared byknown methods; in the presence of a suitably selected coupling agentsuch as EDCl, HATU, PyBOP, and the like; in the presence of a suitablyselected organic amine base such as pyridine, DIEA, Et₃N, and the like;neat or in a suitably selected solvent such as DMF, DCM, THF, and thelike; to yield the corresponding compound of formula (I-B).

Compounds of formula (I-A) may be prepared as described in Scheme 3,below.

Accordingly, a suitably substituted compound of formula (XV), preparedfor example as described herein, is reacted with a suitably substitutedcompound of formula (XVI), wherein LG¹ is a suitably selected leavinggroup such as Br, Cl, and the like, a known compound or compoundprepared by known methods; in the presence of a suitably selected basesuch as K₂CO₃, Na₂CO₃, and the like; in a suitably selected solvent suchas DMF, ACN, and the like; at about room temperature; to yield thecorresponding compound of formula (XVII).

The compound or formula (XVII) is reacted to effect ring closure,according to known method, for example by reacting with NH₄OAc; in thepresence of AcOH; in a suitably selected solvent such as toluene, andthe like; at an elevated temperature, for example at about 110° C.; toyield the corresponding compound of formula (I-Aa).

Compounds of formula (I) wherein R⁴ is halogen may be prepared asdescribed in herein, by reacting a suitably substituted compound offormula (I-Aa) with a suitably selected halogenating agent such as NCS(for chloro), NBS (for bromo), NIS (for iodo), Selectfluor (forfluoro),and the like, in a suitably selected solvent such as DCM, DCE, ACN, THF,Et₂O, and the like; to yield the corresponding compound of formula (I-A)wherein R⁴ is the corresponding halogen.

Compounds of formula (I) wherein R¹ is 1,2,3,4-tetrazol-1-yl mayalternatively be prepared as described in Scheme 4, below.

Accordingly, a suitably substituted compound of formula (XX), a compoundof formula (I) wherein R¹ is NH₂, prepared as described herein, isreacted with a suitably selected source of azides such as TMSN₃, NaN₃,and the like; in the presence of trimethoxymethyl in acetic acid; at anelevated temperature, for example to a temperature of about 80° C.; toyield the corresponding compound of formula (It).

One skilled in the art will recognize that compounds of formula (I)wherein R¹ is a nitrogen bound ring structure (other than1,2,3,4-tetrazol-1-yl exemplified above) may be similarly prepared, byreacting a suitably substituted compound of formula (XX), prepared asdescribed herein, with a suitably selected reagent, to yield the desiredring closure at the terminal NH₂ group, according to known methods, aswould be readily recognized by those skilled in the art.

One skilled in the art will further recognize that various substituentgroups and/or functional groups on said substituent groups (for example—OH, —NH₂, etc.) may be protected prior to any reaction step describedabove, and then de-protected at a later step in the synthesis, as wouldbe desirable or necessary, according to methods well known to thoseskilled in the art.

As more extensively provided in this written description, terms such as“reacting” and “reacted” are used herein in reference to a chemicalentity that is any one of: (a) the actually recited form of suchchemical entity, and (b) any of the forms of such chemical entity in themedium in which the compound is being considered when named.

One skilled in the art will recognize that, where not otherwisespecified, the reaction step(s) is performed under suitable conditions,according to known methods, to provide the desired product. One skilledin the art will further recognize that, in the specification and claimsas presented herein, wherein a reagent or reagent class/type (e.g. base,solvent, etc.) is recited in more than one step of a process, theindividual reagents are independently selected for each reaction stepand may be the same of different from each other. For example whereintwo steps of a process recite an organic or inorganic base as a reagent,the organic or inorganic base selected for the first step may be thesame or different than the organic or inorganic base of the second step.

Further, one skilled in the art will recognize that wherein a reactionstep of the present invention may be carried out in a variety ofsolvents or solvent systems, said reaction step may also be carried outin a mixture of the suitable solvents or solvent systems.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

One skilled in the art will further recognize that the reaction orprocess step(s) as herein described are allowed to proceed for asufficient period of time until the reaction is complete, as determinedby any method known to one skilled in the art, for example,chromatography (e.g. HPLC). In this context a “completed reaction orprocess step” shall mean that the reaction mixture contains asignificantly diminished amount of the starting material(s)/reagent(s)and a significantly reduced amount of the desired product(s), ascompared to the amounts of each present at the beginning of thereaction.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any amountor range therein.

Examples of suitable solvents, bases, reaction temperatures, and otherreaction parameters and components are provided in the detaileddescriptions which follow herein. One skilled in the art will recognizethat the listing of said examples is not intended, and should not beconstrued, as limiting in any way the invention set forth in the claimswhich follow thereafter.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be measured in texts such as T. W. Greene & P. G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,1991.

As used herein, unless otherwise noted, the term “oxygen protectinggroup” shall mean a group which may be attached to an oxygen atom toprotect said oxygen atom from participating in a reaction and which maybe readily removed following the reaction. Suitable oxygen protectinggroups include, but are not limited to, acetyl, benzoyl,t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like.Other suitable oxygen protecting groups may be measured in texts such asT. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,John Wiley & Sons, 1991.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Additionally, chiral HPLC against a standard may be used to determinepercent enantiomeric excess (% ee). The enantiomeric excess may becalculated as follows

[(Rmoles−Smoles)/(Rmoles+Smoles)]×100%

where Rmoles and Smoles are the R and S mole fractions in the mixturesuch that Rmoles+Smoles=1. The enantiomeric excess may alternatively becalculated from the specific rotations of the desired enantiomer and theprepared mixture as follows:

ee=([α-obs]/[α-max])×100.

3. Utility

The compounds of the present invention are useful for the treatmentand/or prophylaxis of thromboembolic disorders, inflammatory disordersand diseases or conditions in which factor XIa and/or plasma kallikreinactivity is implicated.

In some embodiments, the present invention is directed to methods forthe treatment and/or prophylaxis of a thromboembolic disorder comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of a least one of the compounds asdescribed herein, or a stereoisomer, isotopologue, or pharmaceuticallyacceptable salt thereof.

As used herein, the term “thromboembolic disorders” includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis. In some embodiments, the term“thromboembolic disorders” includes acute coronary syndrome, stroke,deep vein thrombosis, and pulmonary embolism. In some embodiments, the“thromboembolic disorders” include hereditary angioedema (HAE) anddiabetic macular edema (DME).

In some embodiments, the present invention is directed to methods forthe treatment and/or prophylaxis of an inflammatory disorder comprising:administering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, isotopologue, orpharmaceutically acceptable salt thereof. Examples of the inflammatorydisorders include, but are not limited to, sepsis, acute respiratorydistress syndrome, and systemic inflammatory response syndrome.

In some embodiments, the present invention is directed to methods forthe treatment and/or prophylaxis of a disease or condition in whichplasma kallikrein activity is implicated, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a stereoisomer, isotopologue, or pharmaceuticallyacceptable salt thereof. The diseases or conditions in which plasmakallikrein activity is implicated include, but are not limited to,impaired visual acuity, diabetic retinopathy, diabetic macular edema,hereditary angioedema, diabetes, pancreatitis, nephropathy,cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis,inflammation, septic shock, hypotension, cancer, adult respiratorydistress syndrome, disseminated intravascular coagulation, andcardiopulmonary bypass surgery.

In some embodiments, the present invention provides a method fortreating the primary prophylaxis of a thromboembolic disorder. In someembodiments, the present invention provides a method for the primaryprophylaxis of a thromboembolic disorder wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, ischemic sudden death,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis. In another embodiment, the presentinvention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In some embodiments, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder. In some embodiments,the present invention provides a method for the secondary prophylaxis ofa thromboembolic disorder. wherein the thromboembolic disorder isselected from unstable angina, an acute coronary syndrome, atrialfibrillation, recurrent myocardial infarction, transient ischemicattack, stroke, atherosclerosis, peripheral occlusive arterial disease,venous thrombosis, deep vein thrombosis, thrombophlebitis, arterialembolism, coronary arterial thrombosis, cerebral arterial thrombosis,cerebral embolism, kidney embolism, pulmonary embolism, and thrombosisresulting from medical implants, devices, or procedures in which bloodis exposed to an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the secondaryprophylaxis of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from acute coronary syndrome, stroke, atrialfibrillation and venous thrombosis.

One skilled in the art will recognize that wherein the present inventionis directed to methods of prophylaxis, the subject in need thereof (i.e.a subject in need of prophylaxis) shall include any subject or patient(preferably a mammal, more preferably a human) who has experienced orexhibited at least one symptom of the disorder, disease or condition tobe prevented. Further, a subject in need thereof may additionally be asubject (preferably a mammal, more preferably a human) who has notexhibited any symptoms of the disorder, disease or condition to beprevented, but who has been deemed by a physician, clinician or othermedical profession to be at risk of developing said disorder, disease orcondition. For example, the subject may be deemed at risk of developinga disorder, disease or condition (and therefore in need of prophylaxisor prophylactic treatment) as a consequence of the subject's medicalhistory, including, but not limited to, family history, pre-disposition,co-existing (comorbid) disorders or conditions, genetic testing, and thelike.

The compounds of the present invention are preferably administered aloneto a mammal in a therapeutically effective amount. However, thecompounds of the invention can also be administered in combination withan additional therapeutic agent, as defined below, to a mammal in atherapeutically effective amount. When administered in a combination,the combination of compounds is preferably, but not necessarily, asynergistic combination. Synergy, for example, may occur when the effect(in this case, inhibition of the desired target) of the compounds whenadministered in combination is greater than the additive effect of thecompounds when administered alone as a single agent. In general, asynergistic effect is most clearly demonstrated at suboptimalconcentrations of the compounds. Synergy can be in terms of lowercytotoxicity, increased anticoagulant effect, or some other beneficialeffect of the combination compared with the individual components.Possible favorable outcomes of treatment with a synergistic combinationinclude, but are not limited to, (a) increased efficacy of thetherapeutic effect, (b) ability to administer decreased dosage whileincreasing or maintaining efficacy (which in turn may also result indecreased toxicity and/or adverse side effects), (c) minimized or sloweddevelopment of drug resistance, (d) selective synergism against thebiological target (or efficacy synergism) versus host (toxicityantagonism).

In some embodiments of the present invention, the compound of formula(I) may be administered in combination with one or more anticoagulant,anti-thrombin agent, anti-platelet agent, fibrinolytic, hypolipidemicagent, antihypertensive agent, and/or anti-ischemic agent. Suitableexamples include, but are not limited to warfarin, heparin, aprotinin, asynthetic pentasaccharide, a boroarginine derivative, a boropeptide,heparin, hirudin, argatroban, a thromboxane-A2-receptor antagonist, athromboxane-A2-synthetase inhibitor, a PDE-III inhibitor, a PDE Vinhibitor, an ADP receptor antagonist, an antagonist of the purinergicreceptor P2Y1, an antagonist of the purinergic receptor P2Y12, tissueplasminogen activator and modified forms thereof, anistreplase,urokinase, streptokinase, tenecteplase, lanoteplase, a PAI-I inhibitor,an alpha-2-antiplasmin inhibitor, an anisoylated plasminogenstreptokinase activator complex, a HMG-CoA reductase inhibitor, asqualene synthetase inhibitor, a fibrate, a bile acid sequestrant, anACAT inhibitor, a MTP inhibitor, a lipooxygenase inhibitor, acholesterol absorption inhibitor, a cholesterol ester transfer proteininhibitor, an alpha adrenergic blocker, a beta adrenergic blocker, acalcium channel blocker, a diuretic, a renin inhibitor, anangiotensin-converting enzyme inhibitor, an angiotensin-II-receptorantagonist, an ET receptor antagonist, a Dual ET/A11 antagonist, aneutral endopeptidase inhibitor, a vasopeptidase inhibitor, a Class Iagent, a Class II agent, a Class III agent, a Class IV agent, an IAchinhibitor, an IKur inhibitor and a cardiac glycoside.

By “administered in combination” or “combination therapy” it is meantthat the compound of the present invention and one or more additionaltherapeutic agents are administered concurrently or consecutively to thesubject (preferably mammal, more preferably human) being treated. Whenadministered in combination each component may be administered at thesame time or sequentially in any order at different points in time.Thus, each component may be administered separately but sufficientlyclosely in time so as to provide the desired therapeutic effect. Chou,Theoretical Basis, Experimental Design, and Computerized Simulation ofSynergism and Antagonism in Drug Combination Studies, Pharmacol Rev.,2006, vol. 58, 621-681.

4. Pharmaceutical Compositions

The present invention further comprises pharmaceutical compositionscontaining a compound of formula (I) with a pharmaceutically acceptablecarrier. Pharmaceutical compositions containing one or more of thecompounds of the invention described herein as the active ingredient canbe prepared by intimately mixing the compound or compounds with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending upon the desired route of administration (e.g., oral,parenteral). Thus, for liquid oral preparations such as suspensions,elixirs and solutions, suitable carriers and additives include water,glycols, oils, alcohols, flavoring agents, preservatives, stabilizers,coloring agents and the like, for solid oral preparations, such aspowders, capsules and tablets, suitable carriers and additives includestarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Solid oral preparations may also becoated with substances such as sugars or be enteric-coated so as tomodulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared utilizing aqueous carriers along withappropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe sugar coated or enteric coated by standard techniques. Forparenterals, the carrier will usually comprise sterile water, throughother ingredients, for example, for purposes such as aiding solubilityor for preservation, may be included. Injectable suspensions may also beprepared, in which case appropriate liquid carriers, suspending agentsand the like may be employed. The pharmaceutical compositions hereinwill contain, per dosage unit, e.g., tablet, capsule, powder, injection,teaspoonful and the like, an amount of the active ingredient necessaryto deliver an effective dose as described above. The pharmaceuticalcompositions herein will contain, per unit dosage unit, e.g., tablet,capsule, powder, injection, suppository, teaspoonful and the like, offrom about 0.01 mg to about 1000 mg or any amount or range therein, andmay be given at a dosage of from about 0.05 mg/day to about 1000 mg/day,or any amount or range therein, about 0.1 mg/day to about 500 mg/day, orany amount or range therein, preferably from about 1 mg/day to about 300mg/day, or any amount or range therein.

The dosages, however, may be varied depending upon the requirement ofthe patients, the severity of the condition being treated and thecompound being employed. The use of either daily administration orpost-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms such as tablets,pills, capsules, powders, granules, sterile parenteral solutions orsuspensions, metered aerosol or liquid sprays, drops, ampoules,autoinjector devices or suppositories; for oral parenteral, intranasal,sublingual or rectal administration, or for administration by inhalationor insufflation. Alternatively, the composition may be presented in aform suitable for once-weekly or once-monthly administration; forexample, an insoluble salt of the active compound, such as the decanoatesalt, may be adapted to provide a depot preparation for intramuscularinjection. For preparing solid compositions such as tablets, theprincipal active ingredient is mixed with a pharmaceutical carrier, e.g.conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g. water, toform a solid pre-formulation composition containing a homogeneousmixture of a compound of the present invention, or a pharmaceuticallyacceptable salt thereof. When referring to these pre-formulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective dosage forms such astablets, pills and capsules. This solid pre-formulation composition isthen subdivided into unit dosage forms of the type described abovecontaining from about 0.01 mg to about 1,000 mg, or any amount or rangetherein, of the active ingredient of the present invention. The tabletsor pills of the novel composition can be coated or otherwise compoundedto provide a dosage form yielding the advantage of prolonged action. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer whichserves to resist disintegration in the stomach and permits the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of material can be used for such enteric layers or coatings,such materials including a number of polymeric acids with such materialsas shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of the treatment and/or prophylaxis of thromboembolicdisorders described in the present invention may also be carried outusing a pharmaceutical composition comprising any of the compounds asdefined herein and a pharmaceutically acceptable carrier. Thepharmaceutical composition may contain between about 0.01 mg and about1000 mg of the compound, or any amount or range therein, preferably fromabout 0.05 mg to about 300 mg of the compound, or any amount or rangetherein, more preferably from about 0.1 mg to about 100 mg of thecompound, or any amount or range therein, more preferably from about 0.1mg to about 50 mg of the compound, or any amount or range therein; andmay be constituted into any form suitable for the mode of administrationselected. Carriers include necessary and inert pharmaceuticalexcipients, including, but not limited to, binders, suspending agents,lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.Compositions suitable for oral administration include solid forms, suchas pills, tablets, caplets, capsules (each including immediate release,timed release and sustained release formulations), granules, andpowders, and liquid forms, such as solutions, syrups, elixirs,emulsions, and suspensions. Forms useful for parenteral administrationinclude sterile solutions, emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms may include suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methyl-cellulose and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

To prepare a pharmaceutical composition of the present invention, acompound of formula (I) as the active ingredient is intimately admixedwith a pharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending of the form of preparation desired for administration (e.g.oral or parenteral). Suitable pharmaceutically acceptable carriers arewell known in the art. Descriptions of some of these pharmaceuticallyacceptable carriers may be measured in The Handbook of PharmaceuticalExcipients, published by the American Pharmaceutical Association and thePharmaceutical Society of Great Britain. Methods of formulatingpharmaceutical compositions have been described in numerous publicationssuch as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revisedand Expanded, Volumes 1-3, edited by Lieberman et al; PharmaceuticalDosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al;and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, editedby Lieberman et al; published by Marcel Dekker, Inc.

Compounds of the present invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever treatment or prophylaxis of thromboembolic disorders,inflammatory disorders or diseases or conditions in which plasmakallikrein activity is implicated is required.

The daily dosage of the products may be varied over a wide range fromabout 0.01 mg to about 1,000 mg per adult human per day, or any amountor range therein. For oral administration, the compositions arepreferably provided in the form of tablets containing, 0.01, 0.05, 0.1,0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. An effective amount of the drugmay be ordinarily supplied at a dosage level of from about 0.005 mg/kgto about 10 mg/kg of body weight per day, or any amount or rangetherein. Preferably, the range is from about 0.01 to about 5.0 mg/kg ofbody weight per day, or any amount or range therein, more preferably,from about 0.1 to about 1.0 mg/kg of body weight per day, or any amountor range therein, more preferably, from about 0.1 to about 0.5 mg/kg ofbody weight per day, or any amount or range therein. The compounds maybe administered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, and theadvancement of the disease condition. In addition, factors associatedwith the particular patient being treated, including patient age,weight, diet and time of administration, will result in the need toadjust dosages.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trialsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

5. Combination Therapy

One or more additional pharmacologically active agents may beadministered in combination with the compounds of the invention. Theadditional active agent (or agents) is intended to mean apharmaceutically active agent (or agents) that is active in the body,including pro-drugs that convert to pharmaceutically active form afteradministration, which is different from the compound of formula (I), andalso includes free-acid, free-base and pharmaceutically acceptable saltsof said additional active agents when such forms are sold commerciallyor are otherwise chemically possible. Generally, any suitable additionalactive agent or agents, including but not limited to antihypertensiveagents, additional diuretics, anti-atherosclerotic agents such as alipid modifying compound, anti-diabetic agents and/or anti-obesityagents may be used in any combination with the compound of formula (I)in a single dosage formulation (a fixed dose drug combination), or maybe administered to the patient in one or more separate dosageformulations which allows for concurrent or sequential administration ofthe active agents (co-administration of the separate active agents).

Examples of additional active agents which may be employed include butare not limited to angiotensin converting enzyme inhibitors (e.g,alacepril, benazepril, captopril, ceronapril, cilazapril, delapril,enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril,perindopril, quinapril, ramipril, spirapril, temocapril, ortrandolapril); angiotensin receptor antagonists also known asangiotensin receptor blockers or ARBs (e.g., losartan i.e., COZAAR®,valsartan, candesartan, olmesartan, telmesartan, eprosartan, irbesartanand any of these drugs used in combination with hydrochlorothiazide suchas HYZAAR®); diuretics, e.g. hydrochlorothiazide (HCTZ); potassiumsparing diuretics such as amiloride HCl, spironolactone, epleranone,triamterene, each with or without HCTZ; neutral endopeptidase inhibitors(e.g., thiorphan and phosphoramidon); aldosterone antagonists;aldosterone synthase inhibitors; renin inhibitors (e.g. urea derivativesof di- and tri-peptides (See U.S. Pat. No. 5,116,835), amino acids andderivatives (U.S. Pat. Nos. 5,095,119 and 5,104,869), amino acid chainslinked by non-peptidic bonds (U.S. Pat. No. 5,114,937), di- andtri-peptide derivatives (U.S. Pat. No. 5,106,835), peptidyl amino diols(U.S. Pat. Nos. 5,063,208 and 4,845,079) and peptidyl beta-aminoacylaminodiol carbamates (U.S. Pat. No. 5,089,471); also, a variety of otherpeptide analogs as disclosed in the following U.S. Pat. Nos. 5,071,837;5,064,965; 5,063,207; 5,036,054; 5,036,053; 5,034,512 and 4,894,437, andsmall molecule renin inhibitors (including diol sulfonamides andsulfinyls (U.S. Pat. No. 5,098,924), N-morpholino derivatives (U.S. Pat.No. 5,055,466), N-heterocyclic alcohols (U.S. Pat. No. 4,885,292) andpyrrolimidazolones (U.S. Pat. No. 5,075,451); also, pepstatinderivatives (U.S. Pat. No. 4,980,283) and fluoro- and chloro-derivativesof statone-containing peptides (U.S. Pat. No. 5,066,643); enalkrein; RO42-5892 (CAS Registry Number 126222-34-2, also known as remikiren); A65317 (CAS Registry Number 119625-78-4); CP 80794 (CAS Registry Number119625-78-4, also known as terlakiren)); ES 1005 (CAS Registry Number115404-79-0); ES 8891 (CAS Registry Number 129445-88-1); SQ 34017 (CASRegistry Number 695226-77-8); aliskiren(2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamidehemifumarate); endothelin receptor antagonists; vasodilators (e.g.nitroprusside); calcium channel blockers (e.g., amlodipine, nifedipine,verapamil, diltiazem, felodipine, gallopamil, niludipine, nimodipine,nicardipine); potassium channel activators (e.g., nicorandil, pinacidil,cromakalim, minoxidil, aprilkalim, loprazolam); sympatholitics;beta-adrenergic blocking drugs (e.g., acebutolol, atenolol, betaxolol,bisoprolol, carvedilol, metoprolol, metoprolol tartate, nadolol,propranolol, sotalol, timolol); alpha adrenergic blocking drugs (e.g.,doxazocin, prazocin or alpha methyldopa); central alpha adrenergicagonists; peripheral vasodilators (e.g. hydralazine); lipid loweringagents, e.g., HMG-CoA reductase inhibitors such as simvastatin andlovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drugform and function as inhibitors after administration, andpharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoAreductase inhibitors such as atorvastatin (particularly the calcium saltsold in LIPITOR®), rosuvastatin (particularly the calcium salt sold inCRESTOR®), pravastatin (particularly the sodium salt sold inPRAVACHOL®), and fluvastatin (particularly the sodium salt sold inLESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®),and ezetimibe in combination with any other lipid lowering agents suchas the HMG-CoA reductase inhibitors noted above and particularly withsimvastatin (VYTORIN®) or with atorvastatin calcium; niacin inimmediate-release or controlled release forms, and particularly niacinin combination with a DP antagonist such as laropiprant (TREDAPTIVE®)and/or with an HMG-CoA reductase inhibitor; niacin in immediate-releaseor controlled release forms, and particularly niacin in combination witha DP antagonist such as laropiprant (TREDAPTIVE®) and/or with an HMG-CoAreductase inhibitor; niacin receptor agonists such as acipimox andacifran, as well as niacin receptor partial agonists; metabolic alteringagents including insulin sensitizing agents and related compounds forthe treatment of diabetes such as biguanides (e.g., metformin),meglitinides (e.g., repaglinide, nateglinide), sulfonylureas (e.g.,chlorpropamide, glimepiride, glipizide, glyburide, tolazamide,tolbutamide), thiazolidinediones also referred to as glitazones (e.g.,pioglitazone, rosiglitazone), alpha glucosidase inhibitors (e.g.,acarbose, miglitol), dipeptidyl peptidase inhibitors, (e.g., sitagliptin(JANUVIA®), alogliptin, vildagliptin, saxagliptin, linagliptin,dutogliptin, gemigliptin), ergot alkaloids (e.g., bromocriptine),combination medications such as JANUMET® (sitagliptin with metformin),and injectable diabetes medications such as exenatide and pramlintideacetate; or with other drugs beneficial for the prevention or thetreatment of the above-mentioned diseases including but not limited todiazoxide; and including the free-acid, free-base, and pharmaceuticallyacceptable salt forms of the above active agents where chemicallypossible. Compounds which can be alternatively or additionallyadministered in combination with the compounds of the present inventioninclude, but are not limited to, anticoagulants, anti-thrombin agents,anti-platelet agents, fibrinolytics, hypolipidemic agents,antihypertensive agents, and anti-ischemic agents.

Anticoagulant agents (or coagulation inhibitory agents) that may be usedin combination with the compounds of this invention include warfarin,heparin (either unfractionated heparin or any commercially available lowmolecular weight heparin, for example enoxaparin and dalteparin),aprotinin, synthetic pentasaccharide inhibitors of Factor Xa such asfondaparinux and idraparinux, direct Factor Xa inhibitors such asrivaroxaban, apixaban, betrixaban, edoxaban, otamixaban, direct actingthrombin inhibitors including hirudin, dabigatran, argatroban,ximelagatran, melagatran, lepirudin, desirudin, and bivalirudin, as wellas other factor VIIa inhibitors, Villa inhibitors, DCa inhibitors, Xainhibitors, XIa inhibitors, fibrinogen receptor antagonists (includingabciximab, eptifibatide and tirofiban), TAFI inibitors, and others knownin the art. Factor DCa inhibitors include synthetic active-site blockedcompetitive inhibitors, oral inhibitors and RNA aptamers. These aredescribed in Howard, E L, Becker K C, Rusconi, C P, Becker R C. FactorIXa Inhibitors as Novel Anticoagulents. Arterioscler Thromb Vasc Biol,2007; 27: 722-727.

The term “anti-platelet agents” or “platelet inhibitory agents”, as usedherein, denotes agents that inhibit platelet function, for example, byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include, but are not limited to, the various knownnon-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin,ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam,diclofenac, sulfinpyrazone, and piroxicam, including pharmaceuticallyacceptable salts or prodrugs thereof. Of the NSAIDS, aspirin(acetylsalicylic acid or ASA), and piroxicam are preferred. Othersuitable platelet inhibitory agents include IIb/IIIa antagonists (e.g.,tirofiban, eptifibatide, and abciximab), thromboxane-A2-receptorantagonists (e.g., ifetroban), thromboxane-A2-synthetase inhibitors,phosphodiesterase-III (PDE-III) inhibitors (e.g., dipyridamole,cilostazol), and PDE V inhibitors (such as sildenafil), andpharmaceutically acceptable salts or prodrugs thereof.

The term “anti-platelet agents” or “platelet inhibitory agents”, as usedherein, is also intended to include ADP (adenosine diphosphate) receptorantagonists, preferable antagonists of the purinergic receptors P2Y1 andP2Y12 with P2Y12 being even more preferred. Preferred P2Y12 receptorantagonists include ticlopidine, prasugrel, clopidogrel, elinogrel,ticagrelor and cangrelor, including pharmaceutically acceptable salts orprodrugs thereof. Clopidogrel is an even more preferred agent.Ticlopidine and clopidogrel are also preferred compounds since they areknown to be gentle on the gastro-intestinal tract in use. The compoundsof the present invention may also be dosed in combination withaprotinin.

The term “thrombin inhibitors” or “anti-thrombin agents”, as usedherein, denotes inhibitors of the serine protease thrombin. Byinhibiting thrombin, various thrombin-mediated processes, such asthrombin-mediated platelet activation (that is, for example, theaggregation of platelets, and/or the granular secretion of plasminogenactivator inhibitor-I and/or serotonin), endothelial cell activation,inflammatory reactions, and/or fibrin formation are disrupted. A numberof thrombin inhibitors are known to one of skill in the art and theseinhibitors are contemplated to be used in combination with the presentcompounds. Such inhibitors include, but are not limited to, boroargininederivatives, boropeptides, heparins, hirudin, dabigatran and argatroban,including pharmaceutically acceptable salts and prodrugs thereof.

Boroarginine derivatives and boropeptides include N-acetyl and peptidederivatives of boronic acid, such as C-terminal alpha-aminoboronic acidderivatives of lysine, ornithine, arginine, homoarginine andcorresponding isothiouronium analogs thereof. The term “hirudin”, asused herein, includes suitable derivatives or analogs of hirudin,referred to herein as hirulogs, such as disulfatohirudin.

The term “thrombin receptor antagonists”, also known as proteaseactivated receptor (PAR) antagonists or PAR-1 antagonists, are useful inthe treatment of thrombotic, inflammatory, atherosclerotic andfibroproliferative disorders, as well as other disorders in whichthrombin and its receptor play a pathological role. Thrombin receptorantagonist peptides have been identified based on structure-activitystudies involving substitutions of amino acids on thrombin receptors. InBernatowicz et al, J Med. Chem., vol. 39, pp. 4879-4887 (1996), tetra-and pentapeptides are disclosed as being potent thrombin receptorantagonists, for exampleN-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH₂ andN-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NH₂. Peptidethrombin receptor antagonists are also disclosed in WO 94/03479.Substituted tricyclic thrombin receptor antagonists are disclosed inU.S. Pat. Nos. 6,063,847, 6,326,380 and WO 01/96330. Other thrombinreceptor antagonists include those disclosed in U.S. Pat. Nos.7,304,078; 7,235,567; 7,037,920; 6,645,987; and EP Patent Nos. EP1495018and EP1294714.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (TPA,natural or recombinant) and modified forms thereof, anistreplase,urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factorVIIa inhibitors, PAI-I inhibitors (i.e., inactivators of tissueplasminogen activator inhibitors), alpha-2-antiplasmin inhibitors, andanisoylated plasminogen streptokinase activator complexes, includingpharmaceutically acceptable salts or prodrugs thereof. The termanistreplase, as used herein, refers to anisoylated plasminogenstreptokinase activator complexes. The term urokinase, as used herein,is intended to denote both dual and single chain urokinase, the latteralso being referred to herein as prourokinase. Examples of suitableanti-arrhythmic agents for use in combination with the present compoundsinclude: Class I agents (such as propafenone); Class II agents (such ascarvedilol and propranolol); Class III agents (such as sotalol,dofetilide, aminodarone, azimilide and ibutilide); Class IV agents (suchas ditiazem and verapamil); IAch inhibitors, and IKur inhibitors (e.g.,compounds such as those disclosed in WO01/40231).

6. Definitions

As used herein, unless otherwise noted, “halogen” shall mean chloro,bromo, fluoro and iodo, preferably bromo, fluoro or chloro, morepreferably fluoro or chloro.

As used herein, unless otherwise noted, the term “oxo” shall mean afunctional group of the structure ═O (i.e. a substituent oxygen atomconnected to another atom by a double bond).

As used herein, unless otherwise noted, the term “C_(X-Y)alkyl” whereinX and Y are integers, whether used alone or as part of a substituentgroup, include straight and branched chains containing between X and Ycarbon atoms. For example, C₁₋₄alkyl radicals include straight andbranched chains of between 1 and 4 carbon atoms, including methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.

As used herein, unless otherwise noted, the terms “—(C_(X-Y)alkylene)-and —C_(X-Y)alkylene-” wherein X and Y are integers, shall denote anyC_(X-Y)alkyl carbon chain as herein defined, wherein said C_(X-Y)alkylchain is divalent and is further bound through two points of attachment,preferably through two terminal carbon atoms.

As used herein, unless otherwise noted, the term “hydroxy substitutedC₁₋₄alkyl” shall mean any C₁₋₄alkyl group as defined above substitutedwith at least one hydroxy (—OH) groups, preferably one to three, morepreferably one to two hydroxy groups. Suitable examples include but arenot limited to —CH₂OH, —CH₂CH₂OH, —CH(OH)CH₃, —CH(OH)CH₂OH,—CH₂CH₂CH₂OH, —C(CH₂OH)₃, and the like.

As used herein, unless otherwise noted, the term “fluorinated C₁₋₄alkyl”shall mean any C₁₋₄alkyl group as defined above substituted with one ormore fluoro groups, preferably one to three fluoro group. Suitablyexamples include, but are not limited to —CH₂F, —CHF₂, —CF₃, —CH₂—CF₃,—CF₂—CH₃, —CH₂—CH₂—CH₂F, —CH₂—CH₂—CF₃, —C(CH₃)₂CF₃, —C(CF₃)₃, and thelike.

As used herein, unless otherwise noted, “C_(X-Y)alkoxy” wherein X and Yare integers, shall mean an oxygen ether radical of the above describedstraight or branched chain C_(X-Y)alkyl groups containing between X andY carbon atoms. For example, C₁₋₄alkoxy shall include methoxy, ethoxy,n-propoxy, isopropoxy, n-butyloxy, iso-butyloxy, sec-butyloxy andtert-butyloxy.

As used herein, unless otherwise noted, the term “fluorinatedC₁₋₄alkoxy” shall mean any C₁₋₄alkoxy group as defined above substitutedwith one or more fluoro groups, preferably one to three fluoro group.Suitably examples include, but are not limited to —OCH₂F, —OCHF₂, —OCF₃,—O—CH₂—CF₃, —O—CF₂—CH₃, —O—CH₂—CH₂—CH₂F, —O—CH₂—CH₂—CF₃, —O—C(CH₃)₂CF₃,—O—C(CF₃)₃, and the like.

As used herein, unless otherwise noted, the term “C_(X-Y)cycloalkyl”,wherein X and Y are integers, shall mean any stable X- to Y-memberedmonocyclic, bicyclic, polycyclic, bridged or spiro-cyclic saturated ringsystem, preferably a monocyclic, bicyclic, bridged or spiro-cyclicsaturated ring system. For example, the term “C₃₋₇cycloalkyl” includes,but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, bicyclo[2.2.1]hept-2-yl, and the like.

As used herein, unless otherwise noted, the term “heteroaryl” shalldenote any five or six membered monocyclic aromatic ring structurecontaining at least one heteroatom selected from the group consisting ofO, N and S, optionally containing one to three additional heteroatomsindependently selected from the group consisting of O, N and S; or nineor ten membered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl may be boundthrough any ring atom which results in a stable structure. Suitableexamples include, but are not limited to, furanyl, thienyl, furazanyl,oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, thiazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyrazyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, indolizinyl,isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, imidazo[1,2-a]pyridin-7-yl,[1,2,4]triazolo[4,3-a]pyridin-7-yl, and the like.

As used herein, unless otherwise noted, the term “5 to 6 memberedheteroaryl” shall denote any five or six membered monocyclic aromaticring structure containing at least one heteroatom selected from thegroup consisting of O, N and S, optionally containing one to threeadditional heteroatoms independently selected from the group consistingof O, N and S. Suitably examples include, but are not limited to furyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thidiazolyl,tetrazolyl, pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, dioxinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl,and the like In some embodiments of the present invention, the 5 to 6membered heteroaryl is a 5 membered heteroaryl. In some embodiments ofthe present invention, the 5 to 6 membered heteroaryl is a 6 memberedheteroaryl.

In some embodiments of the present invention, the 5 to 6 memberedheteroaryl is a 5 to 6 membered nitrogen containing heteroaryl. In someembodiments of the present invention, the 5 to 6 membered heteroaryl isa 5 membered nitrogen containing heteroaryl. In some embodiments of thepresent invention, the 5 to 6 membered heteroaryl is a 6 memberednitrogen containing heteroaryl.

The term “5 to 6 membered nitrogen containing heteroaryl” shall denoteany five or six membered monocyclic aromatic ring structure containingat least one N atom, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS. Suitably examples include, but are not limited to pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,triazolyl, thidiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl,and the like.

The term “5 membered heteroaryl” shall denote any five memberedmonocyclic aromatic ring structure containing at least one heteroatomselected from the group consisting of O, N and S, optionally containingone to three additional heteroatoms independently selected from thegroup consisting of O, N and S; whereas the term and “5 memberednitrogen containing heteroaryl” shall denote any five memberedmonocyclic aromatic ring structure containing at least N atom,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S.

The term “6 membered heteroaryl” shall denote any six memberedmonocyclic aromatic ring structure containing at least one heteroatomselected from the group consisting of O, N and S, optionally containingone to three additional heteroatoms independently selected from thegroup consisting of O, N and S; whereas the term and “6 memberednitrogen containing heteroaryl” shall denote any six membered monocyclicaromatic ring structure containing at least N atom, optionallycontaining one to three additional heteroatoms independently selectedfrom the group consisting of O, N and S.

Unless otherwise noted, any heteroaryl (regardless of the number of ringatoms, the number and identity of ring heteroatoms, etc.) may be boundthrough any ring atom which results in a stable structure.

As used herein, unless otherwise noted, the term “9 to 10 memberedheteroaryl” shall denote any nine or ten membered bicyclic aromatic ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to four additionalheteroatoms independently selected from the group consisting of O, N andS. The heteroaryl may be bound through any ring atom which results in astable structure. Suitable examples include, but are not limited to,indolyl, indolizinyl, isoindolinyl, indazolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl,quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl,imidazo[1,2-a]pyridin-7-yl, [1,2,4]triazolo[4,3-a]pyridin-7-yl, and thelike.

In some embodiments of the present invention, the 9 to 10 memberedheteroaryl is a 9 membered heteroaryl. In some embodiments of thepresent invention, the 9 to 10 membered heteroaryl is a 10 memberedheteroaryl.

In some embodiments of the present invention, the 9 to 10 memberedheteroaryl is a 9 to 10 membered nitrogen containing heteroaryl. In someembodiments of the present invention, the 9 to 10 membered heteroaryl isa 9 membered nitrogen containing heteroaryl. In some embodiments of thepresent invention, the 9 to 10 membered heteroaryl is a 10 memberednitrogen containing heteroaryl.

The term “9 to 10 membered nitrogen containing heteroaryl” shall denoteany nine or ten membered bicyclic aromatic ring structure containing atleast one N atom, optionally containing one to four additionalheteroatoms independently selected from the group consisting of O, N andS. The heteroaryl may be bound through any ring atom which results in astable structure. Suitable examples include, but are not limited to,indolyl, indolizinyl, isoindolinyl, indazolyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, imidazo[1,2-a]pyridin-7-yl,[1,2,4]triazolo[4,3-a]pyridin-7-yl, and the like.

The term “9 membered heteroaryl” shall denote any nine membered bicyclicaromatic ring structure containing at least one heteroatom selected fromthe group consisting of O, N and S, optionally containing one to threeadditional heteroatoms independently selected from the group consistingof O, N and S; whereas the term and “9 membered nitrogen containingheteroaryl” shall denote any nine membered bicyclic aromatic ringstructure containing at least N atom, optionally containing one to threeadditional heteroatoms independently selected from the group consistingof O, N and S.

The term “10 membered heteroaryl” shall denote any ten membered bicyclicaromatic ring structure containing at least one heteroatom selected fromthe group consisting of O, N and S, optionally containing one to threeadditional heteroatoms independently selected from the group consistingof O, N and S; whereas the term and “10 membered nitrogen containingheteroaryl” shall denote any ten membered bicyclic aromatic ringstructure containing at least N atom, optionally containing one to threeadditional heteroatoms independently selected from the group consistingof O, N and S.

Unless otherwise noted, any heteroaryl (regardless of the number of ringatoms, the number and identity of ring heteroatoms, etc.) may be boundthrough any ring atom which results in a stable structure.

When a particular group is “substituted” (e.g. C_(X-Y)alkyl, heteroaryl,etc.), that group may have one or more substituents, preferably from oneto five substituents, more preferably from one to three substituents,most preferably from one to two substituents, independently selectedfrom the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a“phenyl-(C₁-C₆alkylene)-amino-carbonyl-(C₁-C₆alkylene)-” substituentrefers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as listed in the Table A, below:

TABLE A Abbreviations Ac = Acetyl (i.e. —C(O)CH₃) AcOH = Acetic Acid ACNor MeCN = Acetonitrile aq. = Aqueous BF₃•Et₂O = Boron trifluoridediethyl etherate BINAP = (2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl)Boc or BOC = tert-Butoxyloxycarbonyl (i.e. —C(O)—O—C(CH₃)₃) B(O-iPr)₃ =Tri(isopropyl) Borate BSA = Bovine Serum Albumin CHAPS =3-[(3-Cholamidopropyl)dimethylammonio]-1- propanesulfonate dba =dibenzylideneacetone DCE = 1,2-Dichloroethane DCM = Dichloromethane DEA= Diethanolamine DIEA or DIPEA = Diisopropylethyl Amine DME = DiabeticMacular Edema DMF = N,N-Dimethylformamide DMSO = Dimethylsulfoxide dppf= 1,1′-Bis(diphenylphosphino)ferrocene EA or EtOAc = Ethyl Acetate EDCI= 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide Ee = EnantiomericExcess ER = End Point Read (assay) equiv. = Equivalents ES or ESI =Electrospray ionization Et = Ethyl EtOH = Ethanol Et₂O = Diethyl EtherFA = Formic Acid FXIa = Factor Xia Grubbs 2^(nd) =(1,3-Bis(2,4,6-trimethylphenyl)-2- generationimidazolidinylidene)dichloro(phenylmethylene) catalyst(tricyclohexylphosphine)ruthenium HAE = Hereditary Angioedema HATU =(1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate Hex = Hexanes HOAc = Acetic Acid HPLC = HighPerformance Liquid Chromatography IPA = Isopropyl Alcohol KIN = KineticRead (assay) KOAc = Potassium Acetate KOt-Bu Potassium tert-ButoxideLC-MS or LC/MS = Liquid chromatography-mass spectrometry Me = MethylMeOH = Methanol 2-Me-THF = 2-Methyl-tetrahydrofuran MOM = Methoxy methylMs or mesyl = Methylsulfonyl (i.e. —SO₂—CH₃) NaOt-Bu = Sodiumtert-Butoxide NBS = N-Bromosuccinimide n-BuLi = n-Butyl Lithium NCS =N-Chlorosuccinimide NH₄OAc = Ammonium Acetate NIS = N-IodosuccinimideNMR = Nuclear Magnetic Resonance OMs or mesylate = Methanesulfonate(i.e. —O—SO₂—CH₃) OTf or tritiate = Trifluoromethanesulfonyl (i.e.—O—SO═—CF₃) OTs or tosylate = p-Toluenesulfonate (i.e. —O—SO₂—(p-methylphenyl)) Pd(dppf)Cl₂ or = [1,1′-Bis(diphenylphosphino)ferrocene]PdCl₂(dppf) Palladium (II) Dichloride PdCl₂(PPh₃)₂ or =Bis(triphenylphosphine)palladium (II) Dichloride Pd(PPh₃)₂Cl₂ Pd₂(dba)₃= Tris(dibenzylideneacetone)dipalladium(0) Pd(PPh₃)₄ =Tetrakis(triphenylphosphine)palladium(0) PE = Petroleum ether Ph =Phenyl PK = Plasma Kallikrein PPh₃ = Triphenylphosphine PyBOP(Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) RFU= Relative Fluorescence Unit sat. = Saturated Selectfluor =1-Chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis SFC(purification) = Supercritical Fluid Chromatography (purification) TBAF= Tetra-n-butylammonium fluoride t-BuOK or = Potassium tert-ButoxideKOt-Bu TEA or Et₃N = Triethylamine Tf or triflyl =Trifluoromethylsulfonyl (i.e. —SO₂—CF₃) TFA = Trifluoroacetic acid TFAA= Trifluoroacetic anhydride THF = Tetrahydrofuran THP =Tetrahydropyranyl TLC = Thin Layer Chromatography TMS = TrimethysilylTMSN₃ = Trimethylsilyl azide Tris (buffer) =2-Amino-2-(hydroxymethyl)-1,3-propanediol Ts or tosyl =—SO₂—(p-methylphenyl) TsCl = Tosyl Chloride

As used herein, the “*” symbol or notation shall denote the presence ofa stereogenic center.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention. It isfurther understood that atropisomers (a specific type of stereoisomerresulting from steric or other hinderances to rotation) are alsoencompassed within the scope of the present invention.

Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similarly, wherein the compound is present as a diastereomer orstereoisomer, the diastereomer or stereoisomer is present at adiastereomeric or stereoisomeric excess of greater than or equal toabout 80%, more preferably, at a diastereomeric or stereoisomeric excessof greater than or equal to about 90%, more preferably still, at adiastereomeric or stereoisomeric excess of greater than or equal toabout 95%, more preferably still, at a diastereomeric or stereoisomericexcess of greater than or equal to about 98%, most preferably, at adiastereomeric or stereoisomeric excess of greater than or equal toabout 99%.

In some embodiments, the present invention is directed to compounds offormula (I) in an enantiomeric excess of one of the R- or S-enantiomers(at the R³ stereocenter denoted with the “*”). In some embodiments ofthe present invention, the compound of formula (I) is present in anenantiomeric excess of one of the R- or S-enantiomers (at the R³stereocenter denoted with the “*”) of about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% orabout 99%. Preferably the compound of formula (I) is present in anenantiomeric excess of one of the R- or S-enantiomers (at the R³stereocenter denoted with the “*”) of greater than or equal to about80%, preferably greater than or equal to about 90%, more preferablygreater than or equal to about 93%, more preferably greater than orequal to about 95%, more preferably greater than or equal to about 97%,more preferably greater than or equal to about 98%, more preferablygreater than or equal to about 99%.

In some embodiments, the present invention is directed to compounds offormula (I) in a diastereomeric or stereoisomeric excess of one of thepossible diastereomers or stereoisomers. In some embodiments of thepresent invention, the compound of formula (I) is present in adiastereomeric or stereoisomeric excess of one of the possiblediastereomers or stereoisomers, of about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98% orabout 99%. Preferably, the compound of formula (I) is present in adiastereomeric or stereoisomeric excess of one of the possiblediastereomers or stereoisomers of greater than or equal to about 80%,preferably greater than or equal to about 90%, more preferably greaterthan or equal to about 93%, more preferably greater than or equal toabout 95%, more preferably greater than or equal to about 97%, morepreferably greater than or equal to about 98%, more preferably greaterthan or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

As used herein, unless otherwise noted, the term “isotopologues” shallmean molecules that differ only in their isotopic composition. Moreparticularly, an isotopologue of a molecule differs from the parentmolecule in that it contains at least one atom which is an isotope (i.e.has a different number of neutrons from its parent atom).

For example, isotopologues of water include, but are not limited to,“light water” (HOH or H₂O), “semi-heavy water” with the deuteriumisotope in equal proportion to protium (HDO or ¹H²HO), “heavy water”with two deuterium isotopes of hydrogen per molecule (d₂O or ²H₂O),“super-heavy water” or tritiated water (T₂O or ³H₂O), where the hydrogenatoms are replaced with tritium (³H) isotopes, two heavy-oxygen waterisotopologues (H₂ ¹⁸O and H₂ ¹⁷O) and isotopologues where the hydrogenand oxygen atoms may each independently be replaced by isotopes, forexample the doubly labeled water isotopologue d₂ ¹⁸O.

It is intended that within the scope of the present invention, any oneor more element(s), in particular when mentioned in relation to acompound of formula (I), shall comprise all isotopes and isotopicmixtures of said element(s), either naturally occurring or syntheticallyproduced, either with natural abundance or in an isotopically enrichedform. For example, a reference to hydrogen includes within its scope ¹H,²H (D), and ³H (T). Similarly, references to carbon and oxygen includewithin their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. Theisotopes may be radioactive or non-radioactive.

Radiolabelled compounds of formula (I) may comprise one or moreradioactive isotope(s) selected from the group of ³H, ¹¹C, ¹⁸F, ¹²²I,¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, the radioactiveisotope is selected from the group of ³H ¹¹C and ¹⁸F.

As used herein, unless otherwise noted, the term “isotopomer” shall meanisomers with isotopic atoms, having the same number of each isotope ofeach element but differing in their position. Isotopomers include bothconstitutional isomers and stereoisomers solely based on isotopiclocation. For example, CH₃CHDCH₃ and CH₃CH₂CH₂D are a pair ofconstitutional isotopomers of n-propane, whereas (R)-CH₃CHDOH and(S)-CH₃CHDOH or (Z)-CH₃CH═CHD and (E)-CH₃CH═CHD are examples of isotopicstereoisomers of ethanol and n-propene, respectively.

It is further intended that the present invention includes the compoundsdescribed herein, including all isomers thereof (including, but notlimited to stereoisomers, enantiomers, diastereomers, tautomers,isotopologues, and the like).

As used herein, unless otherwise noted, the term “isolated form” shallmean that the compound is present in a form which is separate from anysolid mixture with another compound(s), solvent system or biologicalenvironment. In an embodiment of the present invention, the compound offormula (I) is present in an isolated form.

As used herein, unless otherwise noted, the term “substantially pureform” shall mean that the mole percent of impurities in the isolatedcompound is less than about 5 mole percent, preferably less than about 2mole percent, more preferably, less than about 0.5 mole percent, mostpreferably, less than about 0.1 mole percent. In an embodiment of thepresent invention, the compound of formula (I) is present as asubstantially pure form.

As used herein, unless otherwise noted, the term “substantially free ofa corresponding salt form(s)” when used to described the compound offormula (I) shall mean that mole percent of the corresponding saltform(s) in the isolated base of formula (I) is less than about 5 molepercent, preferably less than about 2 mole percent, more preferably,less than about 0.5 mole percent, most preferably less than about 0.1mole percent. In an embodiment of the present invention, the compound offormula (I) is present in a form which is substantially free ofcorresponding salt form(s).

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts”. Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts include,but are not limited to, the following: acetate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: acids including acetic acid, 2,2-dichloroacetic acid,acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuricacid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid,(±)-DL-lactic acid, lactobionic acid, maleic acid, (±)-L-malic acid,malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid.

Representative bases which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: bases including ammonia, L-arginine, benethamine, benzathine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment. Preferably, the subject has experiencedand/or exhibited at least one symptom of the disease or disorder to betreated and/or prevented.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient, preferably a mammal, more preferably a human, forthe purpose of combating a disease, condition, or disorder and includesthe administration of a compound of the present invention to prevent theonset of the symptoms or complications, alleviate the symptoms orcomplications, slow the progression of the disease or disorder, oreliminate the disease, condition, or disorder. The terms “treating” or“treatment” further include: (a) inhibiting the disease-state, i.e.,arresting its development, and/or (b) relieving the disease-state, i.e.,causing regression of the disease state.

As used herein, “prevention” covers the preventive treatment of asubclinical disease-state in a mammal, particularly in a human, aimed atreducing the probability of the occurrence of a clinical disease-state.Patients are selected for preventative therapy based on factors that areknown to increase risk of suffering a clinical disease state compared tothe general population.

As used herein, “prophylaxis” is the protective treatment of a diseasestate to reduce and/or minimize the risk and/or reduction in the risk ofrecurrence of a disease state by administering to a patient atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, isotopologue, or a pharmaceuticallyacceptable salt, thereof. Patients may be selected for prophylaxistherapy based on factors that are known to increase risk of suffering aclinical disease state compared to the general population. Forprophylaxis treatment, conditions of the clinical disease state may ormay not be presented yet. “Prophylaxis” treatment can be divided into(a) primary prophylaxis and (b) secondary prophylaxis. Primaryprophylaxis is defined as treatment to reduce or minimize the risk of adisease state in a patient that has not yet presented with a clinicaldisease state, whereas secondary prophylaxis is defined as minimizing orreducing the risk of a recurrence or second occurrence of the same orsimilar clinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

As used herein, the terms “combination” and “pharmaceutical combination”refer to either: 1) a fixed dose combination in one dosage unit form, or2) a non-fixed dose combination, optionally packaged together forcombined administration.

Examples

The following Examples are set forth to aid in the understanding of theinvention and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

Unless otherwise indicated in the examples, all temperature is expressedin Centigrade (° C.). All reactions were conducted under an inertatmosphere at ambient temperature unless otherwise noted. Unlessotherwise specified, reaction solutions were stirred at room temperatureunder a N_(2(g)) or Ar_((g)) atmosphere. Reagents employed withoutsynthetic details are commercially available or made according to knownmethods, for example according to literature procedures. When solutionswere “concentrated to dryness”, they were concentrated using a rotaryevaporator under reduced pressure, when solutions were dried, they weretypically dried over a drying agent such as MgSO₄ or Na₂SO₄. Where asynthesis product is listed as having been isolated as a residue, itwill be understood by those skilled in the art that the term “residue”does not limit the physical state in which the product was isolated andmay include, for example, a solid, an oil, a foam, a gum, a syrup, andthe like.

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

LC-MS: Unless otherwise indicated, the analytical LC-MS system usedconsisted of a Shimadzu LCMS-2020 with electrospray ionization (ESI) inpositive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler,CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector. Thecolumn was a HALO a C18 30*5.0 mm, 2.7 μm. The mobile phase A was watercontaining 0.05% TFA and mobile phase B was acetonitrile containing0.05% TFA. The gradient was from 5% mobile phase B to 100% (95%) in 2.0min, hold 0.7 min, then revert to 5% mobile phase B over 0.05 min andmaintain for 0.25 min. The Column Oven (CTO-20AC) was operated at a40.0° C. The flow rate was 1.5 mL/min, and the injection volume was 1μl. PDA (SPD-M20A) detection was in the range 190-400 nm. The MSdetector, which was configured with electrospray ionization as ionizablesource; Acquisition mode: Scan; Nebulizing Gas Flow: 1.5 L/min; DryingGas Flow: 15 L/min; Detector Voltage: Tuning Voltage+0.2 kv; DLTemperature: 250° C.; Heat Block Temperature: 250° C.; Scan Range:90.00-900.00 m/z. ELSD (Alltech 3300) detector Parameters: Drift TubeTemperature: 60±5° C.; N2 Flow-Rate: 1.8±0.2 L/min. Mobile phasegradients were optimized for the individual compounds. Calculated masscorresponds to the exact mass.

Preparative HPLC: Unless otherwise noted, preparative HPLC purificationswere performed with Waters Auto purification system (2545-2767) with a2489 UV detector. The column was selected from one of the following:Waters C18, 19×150 mm, 5 μm; XBridge Prep OBD C18 Column, 30×150 mm 5μm; XSelect CSH Prep C18 OBD Column, 5 μm, 19*150 mm; XBridge ShieldRP18 OBD Column, 30×150 mm, 5 μm; Xselect CSH Fluoro Phenyl, 30×150 mm,5 μm; or YMC-Actus Triart C18, 30×150 mm, 5 μm. The mobile phasesconsisted of mixtures of acetonitrile (5-95%) in water containing 0.1%FA or 10 mmol/L NH₄HCO₃. Flow rates were maintained at 25 mL/min, theinjection volume was 1200 μL, and the UV detector used two channels 254nm and 220 nm. Mobile phase gradients were optimized for the individualcompounds.

Chiral chromatography: Chiral analytical chromatography was performed onone of Chiralpak AS, AD, Chiralcel OD, OJ ChiralpakIA,IB,IC,ID,IE,IF,IG,IH columns (Daicel Chemical Industries, Ltd.)(R,R)-Whelk-O1, (S,S)-Whelk-O1 columns (Regis technologies, Inc.) CHIRALCellulose-SB, SC, SA columns (YMC Co., Ltd.) as noted, at differentcolumn size (50×4.6 mm, 100×4.6 mm, 150×4.6 mm, 250×4.6 mm, 50×3.0 mm,100×3.0 mm), with percentage of either ethanol in hexane (% EtOH/Hex) orisopropanol in hexane (% IPA/Hex) as isocratic solvent systems, or usingsupercritical fluid (SFC) conditions.

Normal phase flash chromatography: Unless otherwise noted, normal phaseflash column chromatography (FCC) was performed on silica gel withpre-packaged silica gel columns (such as RediSep©), using ethyl acetate(EtOAc)/hexanes, ethyl acetate (EtOAc)/Petroleum ether (b.p. 60-90° C.),CH₂Cl₂/MeOH, or CH₂Cl₂/10% 2N NH₃ in MeOH, as eluent.

¹H NMR: Unless otherwise noted, ¹H NMR spectra were acquired using 400MHz spectrometers (or 300 MHz spectrometers) in DMSO-d₆ solutions. Thenuclear magnetic resonance (NMR) spectral characteristics refer tochemical shifts (6) are expressed in parts per million (ppm).Tetramethylsilane (TMS) was used as internal reference in DMSO-d₆solutions, and residual CH₃OH peak or TMS was used as internal referencein CD₃OD solutions. Coupling constants (J) are reported in hertz (Hz).The nature of the shifts as to multiplicity is reported as s (singlet),d (doublet), t (triplet), q (quartet), dd (double doublet), dt (doubletriplet), m (multiplet), br (broad).

Synthesis Examples: Intermediates Intermediate 1:(3S,9S)-7-(2-Amino-5-chlorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylicacid

Step 1: (S)-2-((Tert-butoxycarbonyl)amino)-5-oxonon-8-enoate

To a solution of Mg (6.5 g, 246.95 mmol, 6.0 equiv.) in THE (300 mL) wasadded 4-bromo-1-butene (6.7 g, 49.25 mmol) and the mixture was stirredat room temperature for 10 min. An additional portion of4-bromo-1-butene was then added (10.0 g, 74.07 mmol) and the resultingmixture was stirred for an additional 2 h. The resulting solution wasadded to a solution of 1-(tert-butyl) 2-methyl(R)-5-oxopyrrolidine-1,2-dicarboxylate (10.0 g, 41.11 mmol, 1.0 equiv.)in THE (300 mL) at −78° C. The mixture was maintained under nitrogenwith stirring at −78° C. for 4 h. The reaction was quenched with NH₄Clsolution (150 mL), then extracted with ethyl acetate (3×400 mL). Thecombined extracts were washed with water, dried over Na₂SO₄, filteredand purified by silica gel chromatography (0-30% EA/PE) to yield methyl(S)-2-((tert-butoxycarbonyl)amino)-5-oxonon-8-enoate as a yellow oil.LC/MS: mass calculated for C₁₅H₂₅NO₅: 299.17, measured: 322.10 [M+Na]⁺.

Step 2: Methyl (2S)-5-(but-3-en-1-yl)pyrrolidine-2-carboxylate

To a solution of methyl(S)-2-((tert-butoxycarbonyl)amino)-5-oxonon-8-enoate (8.0 g, 26.72 mmol,1.0 equiv.) in DCM (100 mL) at −78° C. were added boron trifluorideetherate (22.8 g, 160.65 mmol, 6.0 equiv.) and triphenylsilane (20.9 g,80.26 mmol, 3.0 equiv.). The mixture was maintained under nitrogen withstirring at −78° C. for 0.5 h, then warmed to room temperature stirredfor 2 h. The reaction mixture was cooled to −78° C. and the reactionquenched with NaHCO₃ solution (40 mL), then extracted with DCM (3×300mL). The combined extracts were washed with water, dried over Na₂SO₄,filtered and purified by silica gel chromatography (0-10% MeOH/DCM) toyield methyl (2S)-5-(but-3-en-1-yl)pyrrolidine-2-carboxylate as a yellowoil. LC/MS: mass calculated for C₁₀H₁₇NO₂: 183.13, measured: 184.10[M+H]⁺.

Step 3: Methyl(2S,5S)-1-acryloyl-5-(but-3-en-1-yl)pyrrolidine-2-carboxylate

To a solution of methyl (2S)-5-(but-3-en-1-yl)pyrrolidine-2-carboxylate(4.0 g, 21.83 mmol, 1.0 equiv.) in THE (80 mL) at −78° C. were added TEA(11.0 g, 108.71 mmol, 5.0 eq.) and acryloyl chloride (2.0 g, 22.10 mmol,1.0 equiv.). The mixture was maintained under nitrogen with stirring at−78° C. for 0.5 h, then warmed to room temperature with stirring for 2 hunder N₂. The reaction was quenched with NH₄Cl solution (40 mL), thenextracted with ethyl acetate (3×100 mL). The combined extracts werewashed with water, dried over Na₂SO₄, filtered and purified by silicagel chromatography (0-50% EA/PE) to yield methyl(2S,5S)-1-acryloyl-5-(but-3-en-1-yl)pyrrolidine-2-carboxylate as ayellow oil. LC/MS: mass calculated C₁₃H₁₉NO₃: 237.14, measured: 238.30[M+H]⁺.

Step 4: Methyl(3S,9S)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate

To a solution of methyl(2S,5S)-1-acryloyl-5-(but-3-en-1-yl)pyrrolidine-2-carboxylate (4.5 g,18.96 mmol, 1.0 equiv.) in DCM (100 mL) was added Grubbs catalyst 2ndgeneration (3.2 g, 3.76 mmol, 0.2 equiv.). The mixture was maintainedunder nitrogen stirred at 50° C. overnight under N₂. After cooling toroom temperature, the reaction was quenched with water (50 mL),extracted with ethyl acetate (3×200 mL). The combined extracts werewashed with water, dried over Na₂SO₄, filtered and purified by silicagel chromatography (0-10% MeOH/DCM) to yield methyl(3S,9S)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylateas a yellow oil. LC/MS: mass calculated C₁₁H₁₅NO₃: 209.11, measured:210.25 [M+H]⁺.

Step 5: Methyl(3S,9R)-7-hydroxy-5-oxooctahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate

To a mixture of cuprous chloride (0.3 g, 3.03 mmol, 0.2 equiv.) andBINAP (1.9 g, 3.05 mmol, 0.2 equiv.) in THE (50 mL) was added sodiumtert-butoxide (0.29 g, 3.02 mmol, 0.2 equiv.) under N₂, and the mixturestirred for 30 min. Bis(pinacolato)diboron (4.7 g, 18.51 mmol, 1.2 eq.)was added and the mixture was stirred for 5 min. To the resultingmixture was then added methyl(3S,9S)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate(3.2 g, 15.29 mmol, 1.0 equiv.) in THE (10 mL), followed by addition ofmethanol (0.98 g, 30.59 mmol, 2.0 equiv.). The mixture was stirred atroom temperature overnight under N₂. The mixture was then cooled to 0°C. To the mixture was then added H₂O₂ (17.3 g, 152.58 mmol, 10.0 eq)dropwise. The mixture maintained under nitrogen with stirring at roomtemperature for 3 h under N₂. The reaction mixture was quenched withwater (50 mL), then extracted with ethyl acetate (3×200 mL). Thecombined extracts were washed with water, dried over Na₂SO₄, filteredand purified by silica gel chromatography (0-10% MeOH/DCM) to yieldmethyl(3S,9R)-7-hydroxy-5-oxooctahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylateas a yellow oil. LC/MS: mass calculated C₁₁H₁₇NO₄: 227.12, measured:228.10 [M+H]⁺.

Step 6: Methyl(3S,9R)-5,7-dioxooctahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate

To a solution of methyl(3S,9R)-7-hydroxy-5-oxooctahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate(1.5 g, 6.60 mmol, 1.0 equiv.) in DCM (150 mL) was added pyridiniumchlorochromate (2.8 g, 12.99 mmol, 2.0 equiv.) and the mixture wasstirred at room temperature overnight. The reaction was quenched withwater (50 mL), then extracted with ethyl acetate (3×100 mL). Thecombined extracts were washed with water, dried over Na₂SO₄, filteredand purified by silica gel chromatography (0-10% MeOH/DCM) to yieldmethyl (3S,9R)-5,7-dioxooctahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylateas a yellow solid. LC/MS: mass calculated C₁₁H₁₅NO₄: 225.10, measured:226.10 [M+H]⁺.

Step 7: Methyl(3S,9aR)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate

To a solution of methyl(3S,9aR)-5,7-dioxooctahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate (1.0g, 4.74 mmol, 1.0 equiv.) in DCM (30 mL) was addedN-phenyl-bis(trifluoromethanesulfonimide) (5.1 g, 14.28 mmol, 3.0equiv.) followed by addition of triethylamine (1.9 g, 18.78 mmol, 4.0equiv.). The resulting mixture was stirred at room temperatureovernight. The reaction was quenched with water (20 mL), then extractedwith ethyl acetate (3×100 mL). The combined extracts were washed withwater, dried over Na₂SO₄, filtered and purified by silica gelchromatography (0-30% EA/PE) to yield methyl(3S,9R)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylateas yellow oil. LC/MS: mass calculated C₁₂H₁₄F₃NO₆S: 357.05, measured:358.20 [M+H]⁺.

Step 8: Methyl(3S,9aS)-7-(2-amino-5-chlorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylateTo a solution of ethyl methyl

To a mixture of methyl(3S,9R)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate(902 mg, 2.52 mmol, 1.0 equiv.) and Pd(dppf)Cl₂ (192 mg, 0.25 mmol, 0.1equiv.) in 1,4-dioxane (20 mL) and H₂O (2 mL) was added4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (768 mg,3.03 mmol, 1.2 equiv.), followed by the addition of K₂CO₃ (1.0 g, 7.58mmol, 3.0 equiv.). The resulting mixture was maintained under nitrogenwith stirring at 90° C. for 4 h. After cooling to room temperature, thereaction was quenched with water (50 mL). The resulting mixture wasextracted with ethyl acetate (3×50 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated. The resulting residue was purified by silica gelchromatography (0-10% MeOH/DCM) to yield the methyl(3S,9S)-7-(2-amino-5-chlorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylateas yellow oil. LC/MS: mass calculated for C₁₇H₁₉ClN₂O₃: 334.11,measured: 335.15 [M+H]⁺.

Step 9:(3S,9S)-7-(2-Amino-5-chlorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylicacid

To a solution of methyl(3S,9S)-7-(2-amino-5-chlorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate(732 mg, 2.19 mmol, 1.0 equiv.) in THE (10 mL) and H₂O (5 mL) was addedlithium hydroxide (262 mg, 10.94 mmol, 5.0 equiv.). The reaction wasstirred at room temperature for 2 h. The mixture was adjusted to pH 4,then extracted with ethyl acetate (3×100 mL). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedto yield the(3S,9S)-7-(2-amino-5-chlorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylicacid as a yellow oil. LC/MS: mass calculated for C₁₆H₁₇ClN₂O₃: 320.09,measured: 321.20 [M+H]⁺.

Intermediate 2: (6-amino-3-chloro-2-fluorophenyl)boronic acid

Step 1: N-(4-Chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide

To a mixture of 4-chloro-3-fluorobenzenamine (20 g, 137.398 mmol, 1.00equiv) and Na₂CO₃ (24.7 g, 233.58 mmol, 1.70 equiv) in Et₂O (400 mL) wasadded TFAA (34.6 g, 164.88 mmol, 1.20 equiv) dropwise with stirring at−10° C. The mixture was allowed to warm to room temperature overnight,then diluted with hexane (400 mL) and filtered. The filtrate was washedwith saturated sodium bicarbonate solution (2×200 mL), brine (2×200 mL),dried over Na₂SO₄, and filtered. The filtrate was concentrated to yieldN-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide as white solid.

Step 2: (6-Amino-3-chloro-2-fluorophenyl)boronic acid

To a mixture of N-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (30g, 124.19 mmol, 1.00 equiv) in THE (500 mL) under N₂ was added n-BuLi(99 mL, 248.38 mmol, 2.00 equiv, 2.5 M in hexane) dropwise with stirringat −78° C., and the resulting mixture stirred at −78° C. for 15 min. Thereaction was then allowed to warm to −50° C., over 1 h. The resultingclear brown solution was cooled to −78° C., and then B(O-iPr)₃ (51.3 g,273.21 mmol, 2.20 equiv) was added dropwise. The reaction was stirred at−78° C. for 10 mm, and then the reaction was allowed to warm to roomtemperature. The resulting orange suspension was stirred at roomtemperature for 4 h, then cooled in ice bath and quenched with 1 M HCl(300 mL). The resulting mixture was stirred at room temperatureovernight, then extracted with EtOAc (300 mL×3), dried over Na₂SO₄, andfiltered. The filtrate concentrated. The resulting residue wasrecrystallized (EtOAc/PE: 1/10) to yield6-amino-3-chloro-2-fluorophenylboronic acid as white solid.

Intermediate 3:N-(4-(2-Bromoacetyl)-3-fluoropyridin-2-yl)-N-ethylacetamide

Step 1: N-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)-N-ethylacetamide

Under an insert atmosphere of nitrogen, a mixture ofN-ethyl-N-(3-fluoro-4-iodopyridin-2-yl)acetamide (800 mg, 2.60 mmol,1.00 equiv), tributyl(1-ethoxyvinyl)stannane (1.2 g, 3.32 mmol, 1.3equiv), and Pd(PPh₃)₂Cl₂ (182 mg, 0.260 mmol, 0.1 equiv) in 1,4-dioxane(15 mL) was stirred at 90° C. for 2 h, then concentrated. The residuewas applied onto a silica gel column (80 g, EtOAc/PE: 1/10) to yieldN-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)-N-ethylacetamide as yellowoil.

Step 2: N-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)-N-ethylacetamide

To a mixture ofN-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)-N-ethylacetamide (600 mg,2.38 mmol, 1.0 equiv) in THE (8 mL) with H₂O (4 mL) was added NBS (423mg, 2.38 mmol, 1.0 equiv) and stirred at room temperature for 30 min.The reaction was quenched with water (50 mL) and extracted with ethylacetate (100 mL×3). The combined organic layer was washed with brine,dried over Na₂SO₄, and concentrated to yieldN-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)-N-ethylacetamide as a yellowsolid.

Intermediate 4:N-(4-(2-Bromoacetyl)-3-fluoropyridin-2-yl)-N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)acetamide

Step 1: 1-((3-fluoro-4-iodopyridin-2-yl)amino)-2-methylpropan-2-ol

To a solution of 2,3-difluoro-4-iodopyridine (2.0 g, 8.30 mmol, 1.0equiv.) in DMSO (6 mL) was added 2-amino-2-methyl-1-propanol (4.4 g,49.80 mmol, 6.0 equiv.). The reaction mixture was stirred at 100° C. for4 h, then quenched with water. The reaction mixture was extracted withEA. The organic layers were combined, washed with brine, dried andconcentrated under vacuum to yield2-((3-fluoro-4-iodopyridin-2-yl)amino)-2-methylpropan-1-ol as yellowoil. LC/MS: mass calculated for C₉H₁₂FIN₂O: 310.00, measured: 311.00[M+H]⁺

Step 2:N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-fluoro-4-iodopyridin-2-amine

To a mixture of1-((3-fluoro-4-iodopyridin-2-yl)amino)-2-methylpropan-2-ol (2.2 g, 7.06mmol, 1.0 equiv.) in dichloromethane (21 mL) was added2,6-dimethylpyridine (1.6 mL, 14.12 mmol, 2.0 equiv.) andtrifluoromethanesulfonic acid tert-butyldimethylsilyl ester (2.8 g,10.59 mmol, 1.5 equiv.) at 0° C. The solution was stirred at roomtemperature for 1 h. To the solution was added water and the resultingmixture extracted twice with DCM. The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated under vacuum. Theresulting residue was purified by silica gel chromatography (0-30%EA/PE) to yieldN-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-fluoro-4-iodopyridin-2-amineas a white solid. LC/MS: mass calculated for C₁₅H₂₆FIN₂OSi: 424.08,measured: 425.10 [M+H]⁺.

Step 3:N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-fluoro-4-iodopyridin-2-yl)acetamide

A mixture ofN-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-3-fluoro-4-iodopyridin-2-amine(2.5 g, 5.89 mmol, 1.0 equiv.) in acetic anhydride (30 mL) was stirredat 110° C. overnight. The mixture was concentrated under vacuum. Theresidue was dissolved in EA and washed by NaHCO₃ saturated solution. Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated under vacuum. The resulting residue was purified by silicagel chromatography (0-50% EA/PE) to yieldN-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-fluoro-4-iodopyridin-2-yl)acetamideas a white solid. LC/MS: mass calculated for C₁₇H₂₈FIN₂O₂Si: 466.09,measured: 467.10 [M+H]⁺.

Step 4:N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-fluoro-4-iodopyridin-2-yl)acetamide

To a mixture ofN-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-fluoro-4-iodopyridin-2-yl)acetamide(1.0 g, 2.14 mmol, 1.0 equiv.) in 1,4-dioxane (10 mL) was addedtributyl(1-ethoxyvinyl)stannane (0.87 mL, 2.57 mmol, 1.2 equiv.) andPd(PPh₃)₄ (248 mg, 0.21 mmol, 0.1 equiv.). The flask was evacuated andflushed three times with nitrogen. The resulting solution was stirred at100° C. for 3 h under nitrogen. After cooling to room temperature, tothe reaction mixture was added water and the resulting mixture wasextracted twice with EA. The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated under vacuum. The residue waspurified by Al₂O₃ column (0-20% EA/PE) to yieldN-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(3-fluoro-4-iodopyridin-2-yl)acetamideas a yellow oil. LC/MS: mass calculated for C₂₁H₃₅FN₂O₃Si: 410.24,measured: 411.40 [M+H]⁺.

Step 5:N-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)-N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)acetamide

To a mixture ofN-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-N-(4-(1-ethoxyvinyl)-3-fluoropyridin-2-yl)acetamide(800 mg, 1.95 mmol, 1.0 equiv.) in THE (9 mL) and water (3 mL) was addedN-bromosuccinimide (347 mg, 1.95 mmol, 1.0 equiv.). The solution wasstirred at room temperature for 0.5 h. To the reaction mixture was addedwater, and the resulting mixture was extracted twice with EA. Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated under vacuum to yieldN-(4-(2-bromoacetyl)-3-fluoropyridin-2-yl)-N-(2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)acetamideas a yellow solid. LC/MS: mass calculated for C₁₉H₃₀BrFN₂O₃Si: 460.12,measured: 463.30 [M+H+2]⁺.

Intermediate 5: 2-Bromo-4-chloro-1-(difluoromethoxy)-3-fluorobenzene

Step 1: 2-bromo-4-chloro-3-fluorophenol

To a solution of 2-bromo-3-fluorophenol (5.0 g, 26.18 mmol, 1.0 equiv.)in ACN (200 ml) at 0° C. was added NCS (3.5 g, 26.21 mmol, 1.0 equiv.)and TFA (3.3 ml). The reaction mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated. The residue waspurified by silica gel chromatography (0-20% EA/PE) to yield2-bromo-4-chloro-3-fluorophenol as a yellow oil. LC/MS: mass calculatedfor C₆H₃BrClFO: 223.90, measured: 222.90[M+H]⁻

Step 2: 2-bromo-4-chloro-1-(difluoromethoxy)-3-fluorobenzene

To a solution of 2-bromo-4-chloro-3-fluorophenol (3.7 g, 16.41 mmol, 1.0equiv.) in DMF (60 ml) was added Cs₂CO₃ (10.7 g, 32.84 mmol, 2.0 equiv.)and sodium 2-chloro-2,2-difluoroacetate (5.0 g, 32.80 mmol, 2.0 equiv.).The reaction was stirred overnight at 90° C. After cooling to roomtemperature, the reaction mixture was poured into water (100 mL), thenextracted with EA (3×100 mL). The organic layers were combined, washedwith water (100 ml) and brine (100 ml), dried over Na₂SO₄, filtered andconcentrated. The residue obtained was purified by silica gelchromatography (0-20% EA/PE) to yield2-bromo-4-chloro-1-(difluoromethoxy)-3-fluorobenzene as a colorless oil.¹H NMR (300 MHz, Chloroform-d) δ 7.38 (dd, J=9.0, 7.8 Hz, 1H), 7.05-6.99(m, 1H), 6.55 (t, J=72.5 Hz, 1H).

Intermediate 6: 4-(2-Bromoacetyl)-3-fluorobenzamide

Step 1: 4-(1-ethoxyvinyl)-3-fluorobenzamide

Under an inert atmosphere of nitrogen, a mixture of4-bromo-3-fluorobenzamide (1.0 g, 4.59 mmol, 1.0 equiv),tributyl(1-ethoxyvinyl)stannane (2.2 g, 6.09 mmol, 1.3 equiv), Pd(PPh₃)₄(530 mg, 0.46 mmol, 0.1 equiv) in 1,4-dioxane (15 mL) was stirred at 90°C. for overnight, then concentrated under reduced pressure. Theresulting residue was applied onto a silica gel column (80 g, EtOAc/PE:1/10) to yield 4-(1-ethoxyvinyl)-3-fluorobenzamide as yellow oil.

Step 2: 4-(2-bromoacetyl)-3-fluorobenzamide

To a mixture of 4-(1-ethoxyvinyl)-3-fluorobenzamide (800 mg, 3.82 mmol,1.0 equiv) in THE (10 mL) with H₂O (5 mL) was added NBS (681 mg, 3.83mmol, 1.0 equiv) and the resulting mixture stirred at room temperaturefor 30 min. The reaction was quenched with water (50 mL), and theresulting mixture extracted with ethyl acetate (100 mL×3). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedto yield 4-(2-bromoacetyl)-3-fluorobenzamide as a yellow solid.

SYNTHESIS EXAMPLES: COMPOUNDS OF FORMULA (1) Example 1:(3S,9S*)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one

Step 1: 2-(6-acetamido-2-fluoropyridin-3-yl)-2-oxoethyl(3S,9S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate

To a solution of(3S,9S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylicacid (351 mg, 1.04 mmol, 1.0 equiv.) in DMF (10 mL) was added cesiumcarbonate (197 mg, 0.61 mmol, 0.6 equiv.) and the resulting mixture wasstirred at room temperature for 0.5 h. To the resulting mixture was thenadded N-(5-(2-bromoacetyl)-6-fluoropyridin-2-yl)acetamide (343 mg, 1.25mmol, 1.2 equiv.). The mixture was stirred at room temperature for 2 h.The reaction was quenched with water (20 mL), and the resulting mixturewas extracted with ethyl acetate (3×30 mL). The combined extracts werewashed with water, dried over Na₂SO₄, filtered and purified by silicagel chromatography (0-10% MeOH/DCM) to yield2-(6-acetamido-2-fluoropyridin-3-yl)-2-oxoethyl(3S,9S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylateas a yellow oil. LC/MS: mass calculated for C₂₅H₂₃ClF₂N₄O₅: 532.13,measured: 533.10 [M+H]⁺.

Step 2:N-(5-(2-((3S,9S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2-yl)acetamide

To a solution of 2-(6-acetamido-2-fluoropyridin-3-yl)-2-oxoethyl(3S,9S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate(435 mg, 0.82 mmol, 1.0 equiv.) in toluene (10 mL) and acetic acid (1mL) was added ammonium acetate (629 mg, 9.98 mmol, 10.0 equiv.). Theresulting mixture was stirred at 90° C. for 3 h. After cooling to roomtemperature, the reaction was quenched with water (20 mL), and theresulting mixture extracted with ethyl acetate (3×50 mL). The organiclayers were combined, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue obtained was purified by silica gelchromatography (0-10% methanol/DCM) to yield theN-(5-(2-((3S,9S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2-yl)acetamidea yellow solid. LC/MS: mass calculated for C₂₅H₂₃ClF₂N₆O₂: 512.15,measured: 513.35 [M+H]⁺

Step 3:N-(5-(2-((3S,9S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2-yl)acetamide

To a solution ofN-(5-(2-((3S,9S)-7-(6-amino-3-chloro-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2-yl)acetamide(352 mg, 0.69 mmol, 1.0 equiv.) in acetic acid (10 mL) was addedazidotrimethylsilane (791 mg, 6.87 mmol, 10.0 equiv.), trimethoxymethane(728 mg, 6.86 mmol, 10.0 equiv.). The reaction mixture was then stirredat 65° C. for 3 h. The reaction was quenched with water (30 mL), and theresulting mixture extracted with ethyl acetate (3×30 mL). The organiclayers were combined, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue obtained was purified by silica gelchromatography (0-10% methanol/DCM) to yield theN-(5-(2-((3S,9S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2-yl)acetamideas a yellow solid. LC/MS: mass calculated for C₂₆H₂₂ClF₂N₉O₂: 565.16,measured: 566.35 [M+H]⁺.

Step 4:N-(5-(2-((3S,9S)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-6-fluoropyridin-2-yl)acetamide

To a solution of(3S)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one(230 mg, 0.41 mmol, 1.0 equiv.) in THE (1 mL) was added 4 N HCl solution(1 mL). The resulting mixture was stirred at 50° C. for 3 h. Aftercooling to room temperature, the reaction mixture was diluted with waterand then extracted with EA. The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated to dryness underreduced pressure to yield a residue, which was purified by C18 column(eluent: 5% to 50% (v/v) CH₃CN and H₂O with 0.05% NH₄HCO₃) andchiral-HPLC using a Column: CHIRALPAK IA-3, 4.6*50 mm; 3 um; MobilePhase A: MtBE (0.1% DEA):EtOH=80:20, Mobile Phase B:; Flow rate: 1mL/min to yield(3S,9S*)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-oneas a white solid.

LC/MS: mass calculated for C₂₄H₂₀ClF₂N₉O: 523.14, measured (ES, m/z):524.15 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 11.81 (br, 1H), 9.81 (s, 1H),7.84-8.03 (m, 2H), 7.65 (d, J=8.7 Hz, 1H), 6.98-7.06 (m, 1H), 6.37 (d,J=8.2 Hz, 1H), 6.18-6.26 (m, 2H), 5.72 (s, 1H), 5.03 (d, J=6.1 Hz, 1H),3.43-3.63 (m, 1H), 2.61-2.80 (m, 1H), 2.23-2.39 (m, 1H), 1.87-2.20 (m,6H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −70.04, −70.76, −114.02.

Example 2:4-((3S*,9aS*)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamido)benzoicacid

Step 1: methyl(3*S)-5-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate

To a solution of methyl(3S*)-5-oxo-7-(((trifluoromethyl)sulfonyl)oxy)-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate(500 mg, 1.40 mmol, 1.0 equiv.) in 1,4-dioxane (10 ml) was added KOAc(275 mg g, 2.80 mmol, 2.0 equiv.),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (533 mg,2.10 mmol, 1.5 equiv.), and Pd(dppf)Cl₂ (102 mg, 0.14 mmol, 0.1 equiv.)under N₂. The reaction mixture was then stirred for 4 h at 90° C. Aftercooling to room temperature, the resulting mixture was concentrated toyield methyl(3*S)-5-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylateas a yellow oil, which was used in the next step without furtherpurification. LC/MS: mass calculated for C₁₂H₁₄F₃NO₆S: 335.19, measured:336.20[M+H]⁺

Step 2: methyl(3*S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate

To a solution of 2-bromo-4-chloro-1-(difluoromethoxy)-3-fluorobenzene(500 mg, 1.82 mmol, 1.0 equiv.) in 1,4-dioxane/H₂O (12 ml, 4/1) wasadded((3S*)-3-(methoxycarbonyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-7-yl)boronicacid (459 mg, 1.81 mmol, 1.0 equiv.), K₃PO₄ (770 mg, 3.63 mmol, 2.0equiv.), and Pd(dppf)Cl₂ (133 mg, 0.18 mmol, 0.1 equiv.) under N₂. Thereaction mixture was stirred for 4 h at 90° C. After cooling to roomtemperature, the reaction was quenched with water (50 ml). The resultingmixture was extracted with EA (3×50 mL). The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel chromatography (0-50% EA/PE) to yield methyl(3*S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylateas a yellow oil. LC/MS: mass calculated for C₁₈H₁₇ClF₃NO₄: 403.08,measured: 404.20[M+H]⁺.

Step 3:(3*S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylicacid

To a solution of methyl(3*S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate(540 mg, 1.34 mmol, 1.0 equiv) in THF/H₂O (8 ml, 3/1) at 0° C. was addedLiOH (64 mg, 2.67 mmol, 2.0 equiv). The mixture was then stirred for 1 hat room temperature. The resulting solution was concentrated and thendiluted with water (20 ml). The water layers were adjusted to pH 4-5with 2N HCl and extracted with EA (3×50 mL). The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by reverse C18 column (10-60% H₂O(0.05% TFA)/ACN) to yield(3*S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylicacid as a yellow oil. LC/MS: mass calculated for C₁₇H₁₅ClF₃NO₄: 389.06,measured: 390.20[M+H]⁺.

Step 4: tert-butyl4-((3*S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamido)benzoate

To a solution of(3*S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylicacid (220 mg, 0.56 mmol, 1.0 equiv.) in pyridine (8 ml) was addedtert-butyl 4-aminobenzoate (164 mg, 0.85 mmol, 1.5 equiv.) and EDCl (216mg, 1.13 mmol, 2.0 equiv.) under N₂. The reaction mixture was thenstirred for 3 h at room temperature. The resulting mixture wasconcentrated under reduced pressure. The resulting residue was purifiedby reverse C18 column (15-80% H₂O (0.05% TFA)/ACN) to yield tert-butyl4-((3*S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamido)benzoateas an off-white solid. LC/MS: mass calculated for C₂₈H₂₈ClF₃N₂O₅:564.16, measured: 565.20[M+H]⁺.

Step 5:4-((3*S,9*S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamido)benzoicacid

To a solution of tert-butyl4-((3*S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamido)benzoate(250 mg, 0.49 mmol, 1.0 equiv.) in DCM (10 ml) at 0° C. was added TFA (2ml). The resulting mixture was then stirred for 3 h at room temperature.The resulting mixture was concentrated and purified by reverse C18column (15-80% H₂O (0.05% TFA)/ACN) and then Prep-Chiral-HPLC using a(R, R) WHELK-01, 4.6*50 mm, 3.5 um column (eluent: Hex (0.1%TFA):EtOH=80:20), Flow rate: 1 mL/min to yield4-((3*S,9*S)-7-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamido)benzoicacid as a white solid.

LC/MS: mass calculated for C₂₄H₂₀ClF₃N₂O₅: 508.10, measured (ES, m/z):509.05 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.74 (br, 1H), 10.51 (s,1H), 7.94-7.85 (m, 2H), 7.69-7.71 (m, 2H), 7.66 (t, J=8.7 Hz, 1H),7.29-7.31 (m, 1H), 7.16 (d, J=8.7 Hz, 1H), 5.89 (d, J=1.5 Hz, 1H),4.64-4.54 (m, 1H), 4.12-3.70 (m, 1H), 2.85-2.71 (m, 1H), 2.46-2.32 (m,1H), 2.27-2.13 (m, 4H), 2.13-1.95 (m, 1H), 1.90-1.77 (m, 1H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ −82.29, −114.88.

Additional representative compounds of formula (I) of the presentinvention were similarly prepared according to the procedures asdescribed in the Schemes and Examples herein, selecting and substitutingsuitably selected reagents and reactants, as would be readily recognizedby those skilled in the art.

Example 3:(3S,9aS)-3-(5-(2-amino-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one

LC/MS: mass calculated for C₂₄H₂₁ClFN₉O: 505.15, measured (ES, m/z):506.15 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.18 (br, 1H), 9.84 (s, 1H),7.67-7.80 (m, 4H), 7.41-7.46 (m, 1H), 7.06 (t, J=5.1 Hz, 1H), 6.01-6.05(m, 2H), 5.62 (d, J=1.5 Hz, 1H), 5.08-5.10 (m, 1H), 3.61-3.68 (m, 1H),2.63-2.75 (m, 1H), 1.89-2.29 (m, 7H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−142.41.

Example 4:(3S,9aS)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-3-(5-(2-(ethylamino)-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one

LC/MS: mass calculated for C₂₆H₂₅ClFN₉O: 533.19, measured (ES, m/z):534.15 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.19 (br, 1H), 9.84 (s, 1H),7.67-7.85 (m, 4H), 7.40-7.47 (m, 1H), 7.03 (t, J=5.1 Hz, 1H), 6.44-6.48(m, 1H), 5.61 (d, J=1.4 Hz, 1H), 5.07-5.13 (m, 1H), 3.60-6.70 (m, 1H),3.33-3.42 (m, 2H), 2.64-2.74 (m, 1H), 1.84-2.28 (m, 7H), 1.15 (t, J=7.1Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −143.60.

Example 5:(3S)-3-(5-(2-amino-3-fluoropyridin-4-yl)-4-fluoro-1H-imidazol-2-yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one

LC/MS: mass calculated for C₂₄H₂₀ClF₂N₉O: 523.14, measured (ES, m/z):524.15 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.44 (br, 1H), 9.84 (s, 1H),7.59-7.83 (m, 4H), 6.62-6.71 (m, 1H), 6.27-6.33 (m, 2H), 5.57 (d, J=1.3Hz, 1H), 5.00-5.09 (m, 1H), 3.57-3.66 (m, 1H), 2.58-2.70 (m, 1H),2.03-2.32 (m, 4H), 1.84-1.96 (m, 3H).

Example 6:N-(4-(2-((3S)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-4-fluoro-1H-imidazol-5-yl)-3-fluoropyridin-2-yl)acetamide

LC/MS: mass calculated for C₂₆H₂₂ClF₂N₉O₂: 565.16, measured (ES, m/z):566.10 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.65 (br, 1H), 10.20 (br,1H), 9.84 (s, 1H), 8.11-8.18 (m, 1H), 7.67-7.81 (m, 3H), 7.42 (t, J=5.3Hz, 1H), 5.57 (d, J=1.4 Hz, 1H), 5.00-5.06 (m, 1H), 3.57-3.65 (m, 1H),2.63-2.72 (m, 1H), 2.08-2.31 (m, 7H), 1.78-1.95 (m, 3H).

Example 7:4-(2-((3S,9aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-3-fluorobenzamide

LC/MS: mass calculated for C₂₆H₂₁ClF₂N₈O₂: 550.14, measured (ES, m/z):551.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.15 (br, 1H), 9.79 (s, 1H),7.97-8.07 (m, 2H), 7.80-7.85 (m, 1H), 7.68-7.75 (m, 2H), 7.58-7.61 (m,1H), 7.36-7.50 (m, 2H), 5.50 (s, 1H), 5.16 (d, J=8.2 Hz, 1H), 4.17 (s,1H), 3.71-3.78 (m, 1H), 2.61-2.70 (m, 2H), 2.20-2.32 (m, 2H), 1.95-2.11(m, 3H).

Example 8:4-(2-((3S,9aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-3-fluorobenzamide

LC/MS: mass calculated for C₂₆H₂₁ClF₂N₈O₂: 550.14, measured (ES, m/z):551.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (br, 1H), 9.83 (s, 1H),7.98-8.07 (m, 2H), 7.88-7.97 (m, 1H), 7.67-7.77 (m, 3H), 7.42-7.44 (m,2H), 5.74 (d, J=1.7 Hz, 1H), 5.06-5.13 (m, 1H), 3.45-3.60 (m, 1H),2.65-2.82 (m, 1H), 2.28-2.39 (m, 1H), 1.89-2.19 (m, 6H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −114.02, −114.56.

Example 9:(3S,9aS)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one

LC/MS: mass calculated for C₂₄H₂₁ClFN₉O: 505.15, measured (ES, m/z):506.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (br, 1H), 9.83 (s, 1H),7.93-8.02 (m, 1H), 7.68-7.81 (m, 3H), 6.89-7.06 (m, 1H), 6.14-6.45 (m,3H), 5.52-5.62 (m, 1H), 5.01-5.08 (m, 1H), 3.56-3.72 (m, 1H), 2.61-2.73(m, 1H), 1.78-2.36 (m, 7H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −70.78.

Example 10:(3R,9aS)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one

LC/MS: mass calculated for C₂₄H₂₁ClFN₉O: 505.15, measured (ES, m/z):506.15 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 9.46 (s, 1H), 8.00-8.06(m, 1H), 7.51-7.62 (m, 3H), 7.21 (d, J=3.4 Hz, 1H), 6.48 (dd, J=8.3, 1.9Hz, 1H), 5.60-5.68 (m, 1H), 5.21 (dd, J=7.7, 3.2 Hz, 1H), 4.30-4.42 (m,1H), 3.73-3.83 (m, 1H), 2.61 (d, J=16.4 Hz, 1H), 2.32-2.53 (m, 4H),2.14-2.28 (m, 1H), 1.83-1.98 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d₄) δ−76.93.

Example 11:(3S,9aR)-3-(5-(6-amino-2-fluoropyridin-3-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one

LC/MS: mass calculated for C₂₄H₂₀ClF₂N₉O: 523.14, measured (ES, m/z):524.15 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 11.80 (br, 1H), 9.76 (s, 1H),7.86-8.03 (m, 1H), 7.75-7.86 (m, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.04 (s,1H), 6.28-6.45 (m, 1H), 6.15-6.26 (m, 2H), 5.46 (s, 1H), 5.07-5.11 (m,1H), 4.02-4.21 (m, 1H), 3.65-3.80 (m, 1H), 2.51-2.71 (m, 1H), 2.12-2.29(m, 2H), 1.83-2.10 (m, 4H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ −70.11,−114.02.

Example 12:(3S,9aS)-3-(5-(2-amino-3-fluoropyridin-4-yl)-1H-imidazol-2-yl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one

LC/MS: mass calculated for C₂₄H₂₀ClF₂N₉O: 523.14, measured (ES, m/z):524.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.20 (br, 1H), 9.83 (s, 1H),7.92 (t, J=8.0 Hz, 1H), 7.61-7.77 (m, 2H), 7.45 (s, 1H), 6.99-7.13 (m,1H), 6.05 (s, 2H), 5.73 (s, 1H), 5.00-5.16 (m, 1H), 3.44-3.70 (m, 1H),2.62-2.86 (m, 1H), 2.26-2.42 (m, 1H), 1.85-2.25 (m, 6H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −114.00.

Example 13:(3S,9aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-(hydroxymethyl)pyridin-4-yl)-1H-imidazol-2-yl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one

LC/MS: mass calculated for C₂₅H₂₁ClF₂N₈O₂: 538.14, measured (ES, m/z):539.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (br, 1H), 9.84 (s, 1H),8.33 (d, J=5.0 Hz, 1H), 7.93 (t, J=8.0 Hz, 1H), 7.84 (t, J=5.4 Hz, 1H),7.68 (dd, J=8.6, 1.5 Hz, 1H), 7.52-7.62 (m, 1H), 5.74 (s, 1H), 5.27 (t,J=5.9 Hz, 1H), 5.03-5.14 (m, 1H), 4.55-4.68 (m, 2H), 3.44-3.70 (m, 1H),2.62-2.86 (m, 1H), 2.28-2.40 (m, 1H), 1.84-2.27 (m, 6H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −114.01, −130.14.

Example 14:4-(2-((3S,9aS)-7-(3-chloro-2-fluoro-6-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-3-fluoropicolinicacid

LC/MS: mass calculated for C₂₇H₁₉ClF₅N₇O₃: 619.12, measured (ES, m/z):620.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H), 8.47 (d, J=4.9Hz, 1H), 8.07 (t, J=5.3 Hz, 1H), 7.93 (t, J=8.2 Hz, 1H), 7.63-7.81 (m,2H), 5.77 (s, 1H), 5.07-5.16 (m, 1H), 3.26-3.70 (m, 1H), 2.65-2.85 (m,1H), 2.26-2.42 (m, 1H), 2.03-2.24 (m, 4H), 1.79-2.01 (m, 2H). ¹⁹F NMR(376 MHz, DMSO-d₆) δ −59.68, −114.06, −124.13.

Example 15:4-(2-((3S,9aS)-7-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-3-fluoropicolinicacid

LC/MS: mass calculated for C₂₇H₂₀ClF₄N₇O₃: 601.13, measured (ES, m/z):602.10 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 8.96 (s, 1H), 8.10-8.38(m, 2H), 7.52-7.77 (m, 4H), 5.79 (s, 1H), 5.21 (s, 1H), 3.76-3.89 (m,1H), 2.62-2.78 (m, 1H), 2.11-2.40 (m, 5H), 1.84-2.08 (m, 2H). ¹⁹F NMR(376 MHz, Methanol-d₄) δ −62.51.

Example 16:3S,9aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(quinoxalin-6-yl)-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₂: 518.14, measured (ES, m/z):519.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (s, 1H), 9.84 (s, 1H),8.89 (d, J=1.9 Hz, 1H), 8.82 (d, J=1.9 Hz, 1H), 8.50 (d, J=2.3 Hz, 1H),8.03-8.07 (m, 1H), 7.89-7.98 (m, 2H), 7.66-7.70 (m, 1H), 5.74-5.76 (m,1H), 4.52-4.59 (m, 1H), 3.51-3.62 (m, 1H), 2.67-2.76 (m, 1H), 2.32-2.44(m, 1H), 2.13-2.22 (m, 2H), 1.96-2.27 (m, 3H), 1.76-1.84 (m, 1H). ¹⁹FNMR (376 MHz, DMSO-d₆) δ −114.01

Example 17:(3S,9aR)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-((2-hydroxy-2-methylpropyl)amino)pyridin-4-yl)-1H-imidazol-2-yl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one

LC/MS: mass calculated for C₂₈H₂₉ClFN₉O₂: 577.21, measured (ES, m/z):578.25 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.68 (s, 1H), 7.67-7.80 (m,2H), 7.45-7.66 (m, 3H), 7.19 (t, J=5.8 Hz, 1H), 5.63 (s, 1H), 5.04-5.15(m, 1H), 4.15-4.35 (m, 1H), 3.37 (s, 2H), 2.20-2.47 (m, 5H), 2.00-2.18(m, 2H), 1.69-1.92 (m, 1H), 1.16 (s, 6H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−73.77, −105.50.

Example 18:(3S,9aS)-7-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)-3-(5-(3-fluoro-2-((2-hydroxy-2-methylpropyl)amino)pyridin-4-yl)-1H-imidazol-2-yl)-1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-one

LC/MS: mass calculated for C₂₈H₂₉ClFN₉O₂: 577.21, measured (ES, m/z):578.25 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.27 (br, 1H), 9.84 (s, 1H),7.82-7.68 (m, 4H), 7.45-7.60 (m, 1H), 7.03-7.13 (m, 1H), 5.57-5.66 (m,1H), 5.03-5.16 (m, 1H), 3.55-3.78 (m, 1H), 3.38-3.45 (m, 2H), 2.60-2.78(m, 1H), 2.06-2.37 (m, 4H), 1.82-2.05 (m, 3H), 1.14 (s, 6H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ −66.13, −177.0.

Example 19:(3S,9aS)-N-(4-carbamoyl-3-fluorophenyl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamide

LC/MS: mass calculated for C₂₄H₂₀ClF₂N₇O₃: 527.13, measured (ES, m/z):528.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 9.83 (s, 1H),7.93 (t, J=8.2 Hz, 1H), 7.60-7.72 (m, 3H), 7.48-7.53 (m, 2H), 7.31-7.37(m, 1H), 5.74 (s, 1H), 4.43-4.51 (m, 1H), 3.48-3.56 (m, 1H), 2.64-2.72(m, 1H), 2.31-2.40 (m, 1H), 2.11-2.18 (m, 2H), 1.90-2.01 (m, 3H),1.71-1.80 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −110.93, −114.04.

Example 20:(3S,9aR)-N-(4-carbamoyl-3-fluorophenyl)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamide

LC/MS: mass calculated for C₂₄H₂₀ClF₂N₇O₃: 527.13, measured (ES, m/z):528.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.54 (s, 1H), 9.78 (s, 1H),7.84 (t, J=8.2 Hz, 1H), 7.56-7.73 (m, 3H), 7.50-7.53 (m, 2H), 7.34 (d,J=8.6 Hz, 1H), 5.49 (s, 1H), 4.52 (s, 1H), 4.12-4.20 (m, 1H), 3.70-3.77(m, 1H), 2.60-2.68 (m, 1H), 2.31-2.43 (m, 1H), 2.07-2.20 (m, 3H),1.89-1.95 (m, 1H), 1.62-1.69 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ−110.92, −112.37.

Example 21:(3S,9aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(quinoxalin-6-yl)-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClFN₈O₂: 518.14, measured (ES, m/z):519.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s, 1H), 9.80 (s, 1H),8.80-8.92 (m, 2H), 8.48-8.57 (m, 1H), 8.04-8.08 (m, 1H), 7.91-7.96 (m,1H), 7.80-7.86 (m, 1H), 7.59-7.62 (m, 1H), 5.51 (s, 1H), 4.61-4.64 (m,1H), 4.12-4.24 (m, 1H), 3.72-3.81 (m, 1H), 2.56-2.68 (m, 1H), 2.37-2.46(m, 1H), 2.11-2.27 (m, 3H), 1.95-2.02 (m, 1H), 1.67-1.73 (m, 1H). ¹⁹FNMR (376 MHz, DMSO-d₆) δ −114.01.

Example 22:(3S,9aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClF₃N₈O₂: 556.13, measured (ES, m/z):557.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.23 (s, 1H), 9.84 (s, 1H),8.76 (s, 1H), 8.27-8.32 (m, 1H), 8.08-8.10 (m, 1H), 7.89-7.98 (m, 1H),7.65-7.72 (m, 2H), 7.36 (dd, J=9.4, 2.0 Hz, 1H), 5.73-5.76 (m, 1H),4.47-4.54 (m, 1H), 3.49-3.57 (m, 1H), 2.67-2.78 (m, 1H), 2.29-2.39 (m,1H), 2.11-2.19 (m, 2H), 1.91-2.07 (m, 3H), 1.71-1.82 (m, 1H). ¹⁹F NMR(376 MHz, DMSO-d₆) δ −94.24, −114.03.

Example 23:(3S,9aR)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamide

LC/MS: mass calculated for C₂₅H₂₀ClF₃N₈O₂: 556.13, measured (ES, m/z):557.15 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (s, 1H), 9.79 (s, 1H),8.77 (s, 1H), 8.31 (s, 1H), 8.08-8.11 (m, 1H), 7.84 (t, J=8.2 Hz, 1H),7.69 (d, J=9.4 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.32-7.43 (m, 1H), 5.50(s, 1H), 4.56-4.61 (m, 1H), 4.18-4.21 (m, 1H), 3.71-3.76 (m, 1H),2.54-2.65 (m, 2H), 2.04-2.21 (m, 3H), 1.89-1.99 (m, 1H), 1.64-1.71 (m,1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −94.24, −112.33.

BIOLOGICAL AND FORMULATION EXAMPLES Biological Example 1: Factor XIaInhibition Assay Utilizing a Fluorophore-Quencher Pair Peptide Substrate

A fluorescence intensity (FLINT) based assay was used to monitorinhibition of Factor XIa. The peptide substrate, 5Fam-KLTRAETV-K5Tamra(purchased from New England Peptide) was chosen based on the FXIsequence. Conversion of zymogen FXI to its activated form, FXIa, occursby proteolytic cleavage by FXIa at two sites, Arg146 and Arg180. Thecustom peptide used in this assay was based on the Arg146 cleavage siteof FXI. The peptide substrate was designed with a fluorophore-quencherpair, where the fluorescence is quenched until FXIa cleaves the 8-merpeptide after the Arg residue. The substrate K_(M) was fit to asubstrate inhibition model whereby k_(cat)=0.86 s⁻¹, K_(M)=12.4 μM,K_(i)=61.6 μM with an enzymatic efficiency, and k_(cat)/K_(M)=69523M⁻¹s⁻¹.

The Factor XIa FLINT assay was used with the following5Fam-KLTRAETV-K5Tamra assay buffer: 50 mM Tris, pH 7.5, 100 mM NaCl, 5mM CaCl₂, 0.1 mg/mL BSA, 0.03% CHAPS. Assay buffer was prepared bymixing all ingredients fresh. 5Fam-KLTRAETV-K5Tamra peptide substratewas first prepared at 10 mM in 100% DMSO, then diluted to 3 mM in 100%DMSO. Assay buffer was then added directly to the 3 mM stock ofsubstrate to prepare the 30 μM 2× working concentration (15 μM finalconcentration). The 2× Factor XIa stock solution was prepared bydiluting 6.562 μM stock in 1× assay buffer for a 200 μM working stocksolution (100 μM final concentration).

Test compound(s) were run in an 11-point, 3-fold serial dilution with afinal top compound concentration of 100 nM. Final DMSO in assay was 2%.FXIa was preincubated with compound for 30-minutes and then substratewas added to initiate the reaction. The assay was run with kinetic (KIN)reads at 5 min intervals over 30 minutes. The time course was linearusing 100 μM FXIa greater than 30 minutes. More specifically, the assaywas run as follows:

-   -   100 nL of 0.01 mM test compound was dispensed into black        384-well non-binding Greiner BioOne 784900 plate for 0.1 μM        final concentration;    -   5 μL of 1× assay buffer was dispensed to column 24 (low control)        and 5 μL 2× FactorXIa solution was dispensed to columns 1-23        (column 23 high control);    -   the plate was centrifuged with a “cover” plate at 500 rpm for 1        min    -   the plate was pre-incubated for 30 minutes at room temperature        with plate covered;    -   5 μL of 2× 5Fam-KLTRAETV-K5Tamra peptide substrate was dispensed        into the entire plate, columns 1-24;    -   the plate was centrifuged with a “cover” plate at 500 rpm for 1        min;    -   the plate was read monitoring fluorescence intensity on the BMG        PHERAStar at room temperature, using fluorescence module 485        nm/520 nm.

Percent inhibition (IC₅₀) curves were generated per compound tested, anddata was analyzed using a 4-parameter logistic fit using GeneDataScreener. The relative fluorescence unit (RFU) values were normalized topercent inhibition using the following equation:

% inhibition=((HC−LC)−(compound−LC)/(HC−LC))*100

where LC—low control=mean signal of no Factor XIa or 100% inhibition ofFactor XIa; HC—high control=mean signal of FactorXIa+5Fam-KLTRAETV-K5Tamra peptide substrate with DMSO only.

An 11-point dose response curve for the test compound(s) was generatedusing GENDATA to determine IC50 value based on the following equation:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((log IC ₅₀−X)*HillSlope))

where Y is the % inhibition in the presence of X inhibitorconcentration, Top=high control=mean signal of FactorXIa+5Fam-KLTRAETV-K5Tamra peptide substrate with DMSO only; Bottom=lowcontrol—mean signal of no Factor XIa or 100% inhibition of Factor XIa;HillSlope—Hill coefficient; and IC50=concentration of compound with 50%inhibition in relation to top/high control.

Biological Example 2: Kallikrein Inhibition Assay Utilizing a QuenchedAMC Peptide Substrate

A fluorescence intensity (FLINT) based assay was used to monitorinhibition of human plasma kallikrein. The peptide substrate,Z-Gly-Pro-Arg-AMC (Purchased from Bachem; Catalog #I-1150) was chosenbased on its relatively low K_(M) for kallikrein which enables runningthe assay at lower substrate concentrations to control backgroundfluorescence. The kinetic parameters for this substrate were determinedby fitting titration data to the Michaelis-Menten equation yielding aK_(M)=40 μM, k_(cat)=0.76 s⁻¹, and k_(cat)/K_(M)=18932 M⁻¹s⁻¹.

The Kallikrein FLINT assay was used with the following Z-Gly-Pro-Arg-AMCassay buffer: 50 mM Tris, pH 7.5, 100 mM NaCl, 5 mM CaCl₂, 0.1 mg/mLBSA, 0.03% CHAPS. Assay buffer was prepared by mixing all ingredientsfresh. 2× Z-Gly-Pro-Arg-AMC peptide substrate was prepared by diluting10 mM stock into 1× assay buffer for a 100 μM working concentration (50μM final concentration). The 2× kallikrein stock solution was preparedby diluting 14.76 μM stock in 1× assay buffer for a 4 nM working stocksolution (2 nM final concentration).

Test compound(s) were run in an 11-point, 3-fold serial dilution with afinal top compound concentration of 1 μM. Final DMSO in assay was 2%.Plasma kallikrein was pre-incubated for 30-minute with compound and then50 μM substrate was added to initiate the reaction. The assay was runwith kinetic (KIN) reads at 5 min intervals over 30 minutes. The timecourse was linear using 2 nM kallikrein greater than 30 minutes. Morespecifically, the assay was run as follows:

-   -   100 nL of 0.1 mM test compound was dispensed into black 384-well        non-binding Greiner BioOne 784900 plate for 1 μM final        concentration;    -   5 μL of 1× assay buffer was dispensed to columns 24 (low        control) and 5 μL 2× human kallikrein enzyme solution was        dispensed to columns 1-23 (column 23 high control);    -   the plate was centrifuged with a “cover” plate at 500 rpm for 1        min    -   the plate was pre-incubated for 30 minutes at room temperature        with plate covered;    -   5 μL of 2× Z-Gly-Pro-Arg-AMC peptide substrate was dispensed        into the entire plate, columns 1-24;    -   the plate was centrifuged with a “cover” plate at 500 rpm for 1        min;    -   the plate was read monitoring fluorescence intensity on the BMG        PHERAStar at room temperature, using fluorescence module 340        nm/440 nm.

Percent inhibition (IC₅₀) curves were generated per compound tested, anddata was analyzed using a 4-parameter logistic fit using GeneDataScreener. The relative fluorescence unit (RFU) values were normalized topercent inhibition using the following equation:

% inhibition=((HC−LC)−(compound−LC)/(HC−LC))*100

where LC—low control=mean signal of human kallikrein enzyme or 100%inhibition of human kallikrein enzyme; HC—high control=mean signal ofFactor XIa+Z-Gly-Pro-Arg-AMC peptide substrate with DMSO only.

An 11-point dose response curve for the test compound(s) was generatedusing GENDATA to determine IC₅₀ value based on the following equation:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((log IC ₅₀−X)*HillSlope))

where Y is the % inhibition in the presence of X inhibitorconcentration, Top=high control=mean signal of human kallikreinenzyme+Z-Gly-Pro-Arg-AMC peptide substrate with DMSO only; Bottom=lowcontrol—mean signal of no human kallikrein enzyme or 100% inhibition ofhuman kallikrein enzyme; HillSlope—Hill coefficient; andIC₅₀=concentration of compound with 50% inhibition in relation totop/high control.

Representative compounds of formula (I) of the present invention weretested according to the procedure described in Biological Example 1 andBiological Example 2 above, with results as listed in Table 3, below.

TABLE 3 Biological Activity, Representative Compounds of Formula (I)Factor XIa Factor XIa Kallikrein ID No. IC₅₀ (nM) Ki (nM) IC₅₀ (nM)1 >100 >50 227.9 2 8.9 4.4 12.2 3 60.9 30.4 779.7 4 19.9 9.9 38.7 5 82.141.0 143.7 6 24.2 12.1 160.1 7 55.8 27.9 348.1 8 18.7 9.4 13.9 9 24.312.1 42.8 10 >100 >50 245.9 11 8.8 4.4 29.4 12 9.9 5.0 32.4 13 >100 >50800.8 14 >100 >50 234.6 15 39.9 20.0 61.7 16 20.0 10.0 29.5 17 33.4 16.797.1 18 71.9 35.9 89.8 19 6.9 3.5 14.0 20 >100 >50 801.7 21 13.9 6.9112.4 22 >100 >50 892.1 23 27.0 13.5 57.7

Formulation Example 1 Solid, Oral Dosage Form—Prophetic Example

As a specific embodiment of an oral composition, 100 mg of Compound IDNo. 15 or ID No. 3, prepared as described in Example 1 and 2,respectively, is formulated with sufficient finely divided lactose toprovide a total amount of 580 to 590 mg to fill a size O hard gelcapsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

Throughout this application, various publications are cited. Thedisclosure of these publications is hereby incorporated by referenceinto this application to describe more fully the state of the art towhich this invention pertains.

1. A compound of formula (I)

wherein R¹ is selected from the group consisting of halogen, hydroxy,C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy, fluorinated C₁₋₄alkoxy,cyano, nitro, —NR^(A)R^(B), —C(O)—C₁₋₄alkyl, C₃₋₆cycloalkyl, phenyl and5 to 6 membered heterocyclyl; wherein the C₃₋₆cycloalkyl, phenyl or 5 to6 membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, cyano, C₁₋₄alkyl, fluorinated C₁₋₄alkyl, C₁₋₄alkoxy,fluorinated C₁₋₄alkoxy, —C(O)OH, —C(O)O—(C₁₋₄alkyl), —NR^(A)R^(B),—(C₁₋₄alkylene)-NR^(A)R^(B), C₃₋₇cycloalkyl and 5 to 6 memberedheterocyclyl; and wherein R^(A) and R^(B) are each independentlyselected from the group consisting of hydrogen and C₁₋₄alkyl; a is aninteger from 0 to 3; each R² is independently selected from the groupconsisting of chloro, fluoro, methyl and methoxy; Q is selected from thegroup consisting of

wherein R⁴ is selected from the group consisting of hydrogen, andhalogen; wherein R⁵ is selected from the group consisting of phenyl and5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 memberedheteroaryl is optionally substituted with one to two substituentsindependently selected from the group consisting of halogen, C₁₋₄alkyl,fluorinated C₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH,—C(O)O—(C₁₋₄alkyl), —NR^(C)R^(D), —C(O)—NR^(C)R^(D) and—NR^(C)—C(O)—(C₁₋₂alkyl); and wherein R^(C) and R^(D) are eachindependently selected from the group consisting of hydrogen, C₁₋₂alkyland hydroxy substituted C₁₋₄alkyl; and

wherein R⁶ is selected from the group consisting of phenyl and 9 to 10membered heteroaryl; wherein the phenyl or 9 to 10 membered heteroarylis optionally substituted with one to two substituents independentlyselected from the group consisting of halogen, C₁₋₄alkyl, fluorinatedC₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl),—NR^(C)R^(D), —C(O)—NR^(E)R^(F), and —NR^(C)—C(O)—(C₁₋₂alkyl); whereinR^(E) and R^(F) are each independently selected from the groupconsisting of hydrogen and C₁₋₄alkyl; or a stereoisomer, isotopologue,or pharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein R¹ is selected from the group consisting of halogen, hydroxy,C₁₋₄alkyl, fluorinated C₁₋₂alkyl, C₁₋₄alkoxy, fluorinated C₁₋₂alkoxy,C₃₋₆cycloalkyl, phenyl and 5 to 6 membered heterocyclyl; wherein theC₃₋₆cycloalkyl, phenyl or 5 to 6 membered heterocyclyl is optionallysubstituted with one to two substituents independently selected from thegroup consisting of halogen, hydroxy, C₁₋₄alkyl, fluorinated C₁₋₂alkyl,C₁₋₄alkoxy, fluorinated C₁₋₂alkoxy, —C(O)OH, and —C(O)O—(C₁₋₄alkyl); ais an integer from 0 to 2; each R² is independently selected from thegroup consisting of chloro, fluoro, methyl and methoxy; Q is selectedfrom the group consisting of

wherein R⁴ is selected from the group consisting of hydrogen, andhalogen; wherein R⁵ is selected from the group consisting of phenyl and5 to 6 membered heteroaryl; wherein the phenyl or 5 to 6 memberedheteroaryl is optionally substituted with one to two substituentsindependently selected from the group consisting of halogen, C₁₋₄alkyl,fluorinated C₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH,—C(O)O—(C₁₋₄alkyl), —NR^(C)R^(D), —C(O)—NR^(C)R^(D) and—NR^(C)—C(O)—(C₁₋₂alkyl); and wherein R^(C) and R^(D) are eachindependently selected from the group consisting of hydrogen, C₁₋₂alkyland hydroxy substituted C₁₋₄alkyl; and

wherein R⁶ is selected from the group consisting of phenyl and 9 to 10membered heteroaryl; wherein the phenyl or 9 to 10 membered heteroarylis optionally substituted with one to two substituents independentlyselected from the group consisting of halogen, C₁₋₄alkyl, fluorinatedC₁₋₂alkyl, hydroxy substituted C₁₋₂alkyl, —C(O)OH, —C(O)O—(C₁₋₄alkyl),and —C(O)—NR^(E)R^(F); wherein R^(E) and R^(F) are each independentlyselected from the group consisting of hydrogen and C₁₋₂alkyl; or astereoisomer, isotopologue, or pharmaceutically acceptable salt thereof.3. The compound of claim 1, wherein R¹ is selected from the groupconsisting of fluorinated C₁₋₂alkoxy, and 5 to 6 membered heterocyclyl;wherein the 5 to 6 membered heterocyclyl is optionally substituted withfluorinated C₁₋₂alkyl; a is an integer from 1 to 2; each R² isindependently selected from the group consisting of chloro, and fluoro;Q is selected from the group consisting of

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;wherein R⁵ is selected from the group consisting of phenyl and 6membered heteroaryl; wherein the phenyl or 6 membered heteroaryl isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, hydroxy substitutedC₁₋₂alkyl, —C(O)OH, —NR^(C)R^(D), —C(O)—NR^(C)R^(D) and—NR^(C)—C(O)—(C₁₋₂alkyl); wherein R^(C) and R^(D) are each independentlyselected from the group consisting of hydrogen, C₁₋₂alkyl and hydroxysubstituted C₁₋₄alkyl; and

wherein R⁶ is selected from the group consisting of phenyl and 9 to 10membered heteroaryl; wherein the phenyl or 9 to 10 membered heteroarylis optionally substituted with one to two substituents independentlyselected from the group consisting of halogen, fluorinated C₁₋₂alkyl,—C(O)OH) and —C(O)—NR^(E)R^(F); wherein R^(E) and R^(F) are eachindependently selected from the group consisting of hydrogen andC₁₋₂alkyl; or a stereoisomer, isotopologue, or pharmaceuticallyacceptable salt thereof.
 4. The compound of claim 1, wherein R¹ isselected from the group consisting of difluoro-methoxy,4-(trifluoromethyl)-1,2,3-triazol-1-yl, and 1,2,3,4-tetrazol-1-yl; a isan integer from 1 to 2; each R² is independently selected from the groupconsisting of 2-fluoro and 3-chloro; Q is selected from the groupconsisting of

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;wherein R⁵ is selected from the group consisting of2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-6-amino-pyridin-3-yl,2-((2-hydroxy,2-methyl-n-propyl)-amino)-3-fluoro-pyridin-3-yl,2-carboxy-3-fluoro-pyridin-4-yl,2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-amino-3-fluoro-pyridin-4-yl,2-(ethyl-amino)-3-fluoro-pyridin-4-yl, and2-(methyl-carbonyl-amino)-3-fluoro-pyridin-4-yl; and

wherein R⁶ is selected from the group consisting of 4-carboxy-phenyl,3-fluoro-4-(amino-carbonyl)-phenyl, 2-(difluoro-methyl)-indazol-5-yl,and quinoxalin-6-yl; or a stereoisomer, isotopologue, orpharmaceutically acceptable salt thereof.
 5. The compound of claim 1,wherein R¹ is selected from the group consisting of4-(trifluoromethyl)-1,2,3-triazol-1-yl, and 1,2,3,4-tetrazol-1-yl; a isan integer from 1 to 2; each R² is independently selected from the groupconsisting of 2-fluoro and 3-chloro; Q is

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;wherein R⁵ is selected from the group consisting of2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-6-amino-pyridin-3-yl,2-((2-hydroxy,2-methyl-n-propyl)-amino)-3-fluoro-pyridin-3-yl,2-carboxy-3-fluoro-pyridin-4-yl,2-(hydroxy-methyl)-3-fluoro-pyridin-4-yl, 2-amino-3-fluoro-pyridin-4-yl,2-(ethyl-amino)-3-fluoro-pyridin-4-yl, and2-(methyl-carbonyl-amino)-3-fluoro-pyridin-4-yl; or a stereoisomer,isotopologue, or pharmaceutically acceptable salt thereof.
 6. Thecompound of claim 1, wherein R¹ is selected from the group consisting ofdifluoro-methoxy, and 1,2,3,4-tetrazol-1-yl; a is 2; the two R² are2-fluoro and 3-chloro; Q is

wherein R⁶ is selected from the group consisting of 4-carboxy-phenyl,3-fluoro-4-(amino-carbonyl)-phenyl, 2-(difluoro-methyl)-indazol-5-yl,and quinoxalin-6-yl; or a stereoisomer, isotopologue, orpharmaceutically acceptable salt thereof.
 7. The compound of claim 1,wherein R¹ is selected from the group consisting of difluoro-methoxy,4-(trifluoromethyl)-1,2,3-triazol-1-yl and 1,2,3,4-tetrazol-1-yl; a isan integer from 1 to 2; each R² is independently selected from the groupconsisting of 2-fluoro and 3-chloro; Q is selected from the groupconsisting of

wherein R⁴ is selected from the group consisting of hydrogen and fluoro;wherein R⁵ is selected from the group consisting of2-fluoro-4-(amino-carbonyl)-phenyl, 2-fluoro-6-amino-pyridin-3-yl,2-((2-hydroxy,2-methyl-n-propyl)-amino)-3-fluoro-pyridin-3-yl,2-carboxy-3-fluoro-pyridin-4-yl, 2-amino-3-fluoro-pyridin-4-yl, and2-(ethyl-amino)-3-fluoro-pyridin-4-yl; and

wherein R⁶ is selected from the group consisting of3-fluoro-4-(amino-carbonyl)-phenyl, 2-(difluoro-methyl)-indazol-5-yl,and quinoxalin-6-yl; or a stereoisomer, isotopologue, orpharmaceutically acceptable salt thereof.
 8. The compound of claim 1,selected from the group consisting of4-(2-((3S,9aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl)-1H-imidazol-5-yl)-3-fluorobenzamide;(3S,9aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-N-(2-(difluoromethyl)-2H-indazol-5-yl)-5-oxo-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamide;3S,9aS)-7-(3-chloro-2-fluoro-6-(1H-tetrazol-1-yl)phenyl)-5-oxo-N-(quinoxalin-6-yl)-2,3,5,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxamide;and stereoisomers, isotopologues, and pharmaceutically acceptable saltsthereof.
 9. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 1. 10. (canceled) 11.(canceled)
 12. A method for the treatment of (a) a thromboembolicdisorder; (b) an inflammatory disorder or a disorder; or (c) a diseaseor condition in which plasma kallikrein activity is implicated,comprising administering to a subject in need thereof a therapeuticallyeffective amount of the compound of claim
 1. 13. The method of claim 12,wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders.
 14. The method of claim 12, wherein the thromboembolicdisorder is selected from the group consisting of unstable angina, anacute coronary syndrome, atrial fibrillation, first myocardialinfarction, recurrent myocardial infarction, ischemic sudden death,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from prosthetic valves orother implants, indwelling catheters, stents, cardiopulmonary bypass,hemodialysis, or other procedures in which blood is exposed to anartificial surface that promotes thrombosis.
 15. The method of claim 12,wherein the thromboembolic disorder is selected from the groupconsisting of hereditary angioedema (HAE) and diabetic macular edema(DME).
 16. The method of claim 12, wherein the inflammatory disorder isselected from the group consisting of sepsis, acute respiratory distresssyndrome, and systemic inflammatory response syndrome.
 17. The method ofclaim 12, wherein the disease or condition in which plasma kallikreinactivity is implicated is selected from the group consisting of impairedvisual acuity, diabetic retinopathy, diabetic macular edema, hereditaryangioedema, diabetes, pancreatitis, nephropathy, cardiomyopathy,neuropathy, inflammatory bowel disease, arthritis, inflammation, septicshock, hypotension, cancer, adult respiratory distress syndrome,disseminated intravascular coagulation, and cardiopulmonary bypasssurgery.
 18. (canceled)
 19. (canceled)
 20. (canceled)
 21. (canceled) 22.(canceled)
 23. (canceled)
 24. (canceled)
 25. (canceled)
 26. (canceled)27. (canceled)